Methods for the pulmonary delivery of biological agents

ABSTRACT

Methods of delivering a therapeutic or diagnostic agent in a perfluorochemical liquid carrier are provided. In preferred embodiments, the disclosed methods use compositions in the form of an emulsion or a dispersion for delivery of a biological agent to the pulmonary air passages.

This application is a continuation of Ser. No. 08/479,615, filed Jun. 7,1995, abandoned which is a continuation of Ser. No. 08/424,577, filedApr. 13, 1995 and now U.S. Pat. No. 5,562,608, which is a continuationof Ser. No. 07/920,153, filed Jul. 27, 1992, abandoned, which is acontinuation of Ser. No. 07/495,566, filed Mar. 19, 1990 now abandoned,which is a continuation-in-part of Ser. No. 07/399,943, filed Aug. 28,1989, abandoned.

This invention was made with government support under Small BusinessInnovation Research Program Grant No. 1 R43 CA48611-01 awarded by thePublic Health Service, Department of Health and Human Services. Thegovernment has certain rights in the invention.

TECHNICAL FIELD

The invention relates to methods and means for introducing liquids intothe pulmonary system of patients for the treatment of pulmonary and/orsystemic disease, conditions and/or abnormalities such as, for example,to effect hyperthermic treatment and augmented radiotherapy andchemotherapy of lung cancer. This invention also relates to theemployment of liquid as a means of delivering, through the pulmonary airpassages of a patient, biological agents.

BACKGROUND OF THE INVENTION

In the United States there has been a steady rise in the age-adjustednational death rate from pulmonary related diseases. The overwhelminglypredominant contributor to this trend is long cancer. Currently about 8%of all deaths in the industrialized world are attributed to lung cancer.In the United States, an estimated 155,000 new cases of lung cancer arecurrently diagnosed each year, and about 142,000 will die of thedisease, about 1 death every 4 minutes! Only about 10% of the patientscurrently diagnosed with lung cancer will survive beyond 5 years.

Lung cancer, or bronchial carcinoma, refers strictly to tumors arisingfrom the major airways (bronchi) and pulmonary parenchyma (bronchioles,alveoli, and supporting tissue), as opposed to those metastasizing fromother sites. The four major forms of lung cancer, squamous cellcarcinoma (SCC), adenocarcinoma (AC), large cell anaplastic carcinoma(LCAC), and small cell anaplastic carcinoma (SCAC), account for 98% ofpulmonary malignancies. Although lung cancer can occur anywhere in thelungs, about three-quarters of primary lung cancers occur in and/or onthe bronchial walls within the first three bronchial generations, i.e.,near or proximal to the hilus, the region where the airways and majorvessels enter and leave each lung. A smaller percentage occur in moredistal areas of the parenchyma. Many tumors occur near the carina, atthe junction of the right and left bronchi with the trachea, presumedlydue to increased deposition of inhaled carcinogens. Squamous cellcarcinoma tumors, the most common histological type, making up 30-40% oflung tumors, arise inside the surface layer of the bronchial wall andthen invade the wall and adjacent structures. Squamous cell carcinomastend to be relatively localized with less tendency than the other lungcancer tumors to metastasize. Adenocarcinoma tumors, also comprising30-40% of lung cancers, occur in the mid- to outer third of the lung inabout three-quarters of the cases. Adenocarcinomas tend to metastasizewidely and frequently to other lung sites, the liver, bone, kidney, andbrain. Small cell cancer, accounting for about 20% of all lung cancer,is the most aggressively metastatic and rapidly growing, and can beginnear the hilus or in the lung periphery. Large cell tumors account foronly a few percent of lung cancer and can occur anywhere in the lung.“Local failure,” where primary tumors spread to mediastinal lymph nodes,pleura, adrenal glands, bone, and brain, is common with adenocarcinoma,small cell anaplastic carcinoma, and large cell anaplastic carcinoma,and less so in squamous cell carcinoma.

The current “curative” treatment for lung cancer is surgery, but theoption for such a cure is given to very few. Only about 20% of lungcancer is resectable, and out of this number less than half will survivefive years. Radiation therapy (RT) is the standard treatment forinoperable non-small cell cancer, and chemotherapy (alone or withradiation therapy) is the treatment of choice for small cell and otherlung cancer with wide metastasis. Patients with clinically localized buttechnically unresectable tumors represent a major problem for theradiotherapist, accounting for an estimated 40% of all lung cancercases.

Adjunctive hyperthermia, the use of deep heating modalities to treattumors, is being used increasingly to augment the therapeutic efficacyof radiotherapy and chemotherapy in cancer treatment. It has beenestimated that eventually “hyperthermia will be indispensable for 20 to25% of all cancer patients” [1; see the appended listing of literaturecitations]. Hyperthermia clinical research is increasingly showing theimportance of using specialized heating equipment to treat specificanatomical locations and sites rather than devices with moregeneral-purpose heating capabilities. Unfortunately, currenthyperthermia devices are ill-suited to providing deep, localized heatingof lung cancer. Because of this limitation, very few applications oflocalized lung hyperthermia have been recorded in the literature [2].

Kapp [8] has shown that, in terms of absolute numbers of patients(15,000 in 1987), more lung cancer patients would benefit from effectivelocal hyperthermia than in any other cancer category, with the possibleexception of prostate carcinoma. Because of the present difficulty ofheating tumors locally in a controlled fashion in the center of thethorax, the techniques most commonly attempted for lung cancerhyperthermia to date have been whole-body hyperthermia (WBH), andradio-frequency (RF) heating of locoregional lung areas [2,9]. Whilewhole-body hyperthermia has produced some encouraging results incombination with chemotherapy, the technique is unsatisfactory since itproduces significant systemic toxicity and mortality, and because thethermal dose is limited due to long induction times (warmup) and theneed to maintain core temperature below 42° C. The electromagnetic (EM)approaches to lung heating have also been disappointing, due to theunpredictability of the heating patterns produced, the difficulty ofmeasuring intratumoral temperatures in electromagnetic fields, thepropensity of radio-frequency heating to preferentially heat superficialfat, and because of the physical inability of electromagnetic modalitiesto produce small focal volumes. The modern microwave body-surroundingarray systems also suffer from difficulties associated with localizationand predictability of heating, thermometry artifacts, and heat spikes atfat muscle interfaces.

Because of its characteristically small wavelengths, therapeuticultrasound has the best capability for providing local heating in thebody of all the conventionally used hyperthermia modalities. Focused andunfocused ultrasound beams are routinely used clinically to successfullyprovide localized hyperthermia to many tumors residing in soft tissuesand organs. However, the presence of air in the lung has precluded thisvaluable energy source from being applied to lung hyperthermia.

Thus, the need for a means of delivering safe, effective, andwell-tolerated localized heating to lung tumors is clear. The inventionsolves this problem, in the preferred embodiment, by an unconventionaluse of “breathable liquids” (e.g., perfluorocarbon liquids) andtherapeutic ultrasound.

As used herein, the phrase “breathable liquids” refers to liquids whichhave the ability to deliver oxygen into, and to remove carbon dioxidefrom, the pulmonary system (i.e., the lungs) of patients. Examples ofbreathable liquids include, but are not limited to, saline, silicon andvegetable oils, perfluorochemicals, and the like. One of thepresently-preferred breathable liquids is perfluorocarbon liquids.

Perfluorocarbon (also referred to herein as “PFC”) liquids are derivedfrom common organic compounds by the replacement of all carbon-boundhydrogen atoms with fluorine atoms. They are clear, colorless, odorless,nonflammable, and essentially insoluble in water. They have extremelyhigh dielectric strength and resistivity. They are denser than water andsoft tissue, have low surface tension and, for the most part, lowviscosity. Perfluorocarbon liquids appear to have the lowest soundspeeds of all liquids and are also unique in their high affinity forgases, dissolving up to 20 times as much O₂ and over three times as muchCO₂ as water. Like other highly inert carbon-fluorine materials whichare widely used in medicine (e.g., in drugs, Teflon implants, bloodoxygenator membranes, etc.), perfluorocarbon liquids are extremelynontoxic and biocompatible. For a review, see: Biro, P. B., and P.Blais, Perfluorocarbon blood substitutes, in CRC Critical Reviews inOncology/Hematology, Vol. 6, No. 4, pp. 311-374, 1987, which is herebyincorporated by reference.

To date, about 300 liquid compounds have been investigated for blood-gasexchange applications [4]. Those liquids which have evolved asartificial blood substitutes are complex perfluorocarbon liquid-basedaqueous emulsions containing various chemical stabilizers and viscositymodifiers, along with conventional parenteral additives (glucose,electrolytes, starch, and buffers). Compatibility with blood and asurprising lack of major adverse effects have been demonstrated inseveral animal species. The first administration of perfluorocarbonliquid blood substitute (Fluosol-DA, one of four commercial bloodsubstitutes now available) to human volunteers occurred in 1978 [10],with the first clinical use taking place shortly after in 1979 [11,12].Subsequently, numerous other studies have been carried out in Japan, theUnited States, Canada, and Europe that have confirmed the comparativelybenign impact of infusing significant amounts (some tests used liters)of the perfluorocarbon/water emulsions directly into the systemic bloodcirculation [13,14,15]. The blood substitutes are not yet ready forgeneral clinical systemic use for two reasons: a) the requirement toform an emulsion to suspend the perfluorocarbon particles significantlyreduces the volume fraction of the gas carrier (the perfluorocarbon),thus large volumes must be infused, and b) the emulsion graduallycoalesces as it circulates, leading to premature removal of many of thesynthetic constituents from the blood. However, studies are currentlyongoing in a number of clinically related therapeutic perfluorocarbonapplications primarily taking advantage of the oxygen carrying capacityof blood substitute emulsions [16,17,18,19].

It was first demonstrated that mammals submerged in hyperoxygenatedsaline could breathe liquid and successfully resume gas breathing in1962 [20]. However, this approach to liquid ventilation (LV) waseventually abandoned, due to the practical difficulties of dissolvingsufficient quantities of O₂ in saline (done under high pressure), andbecause saline rinses away much of the surfactant lining the lungalveoli [21]. These problems were overcome in 1966, by Dr. Leland Clark[22], who was the first to use perfluorocarbon liquids (now oxygenatedat atmospheric pressure) to support the respiration of mice, cats, andpuppies. The extreme biocompatability and suitable properties of certainperfluorocarbon liquids has subsequently led to a significant body ofongoing research yielding promising clinical applications.

To date it has been clearly established that mammals can breathe (totalventilation support) oxygenated perfluorocarbon liquids for long periods(>3 hours) and return to gas breathing without untoward long-termeffects [23, 24]. In addition, studies have also shown that no adversemorphological, biochemical, or histological effects are seen afterperfluorocarbon ventilation [24, 25, 26].

Perfluorocarbon liquids have also been investigated for lung lavage(washing) [27], and have been found to be effective for rinsing outcongestive materials associated with Respiratory Distress syndrome (RDS)in adult humans [28]. While total respiratory support of both lungs viaperfluorocarbon liquids is not without side effects, they are minor andtransient (mild acidosis, lower blood pO₂, and increased pulmonaryvascular resistance and decreased lung compliance) [3,29,30,31]. Otherbiomedical applications of perfluorocarbon liquid ventilation have alsoreceived serious research effort [32,33].

Pertinent to convective lung hyperthermia, i.e., lung heating by therepetitious infusion and removal of hot liquids to and from the lung,studies of the physiological heat exchange occurring from high- andlow-temperature perfluorocarbon ventilation of animals have also beenperformed [30,41,42]. These studies have involved complete-lung liquidheating and cooling, and have been done at only moderate temperatures,but have illuminated and quantified many relevant physiologicalresponses and systemic temperature effects. A very recent study [43]reporting hyperthermic (to 45° C.) convection heating of lungs involvedsustained heating of surgically isolated dog lung lobes via heated bloodperfusion, i.e., heating induced from the blood side rather than theairway side. Taking measurements of lung edema, compliance, perfusionpressure, and serotonin uptake during 2-hour sustained hyperthermia(done at 37.6°, 40.7°, and 44.5° C., time-averaged lung temperatures),no significant changes in lung parameters were found other than expectedincreases in perfusion pressure with temperature. The authors concludethat a normal lung appears to tolerate well the sustained heatingregimens appropriate for cancer hyperthermia applications.

However, the problem of how to effect controlled and sufficientlylocalized hyperthermia of malignant lung tissue has, until now, remainedunsolved.

As stated earlier, one way of treating pulmonary-related diseases,conditions and/or abnormalities is by the implementation ofchemotherapeutic agents, either alone or in conjunction with othertherapeutic techniques (e.g., radiotherapy). However, there are manyproblems existing when employing conventional techniques ofchemotherapy. For example, in the presence of lung disease andintrapulmonary shunting, systemically administered drugs areineffectually delivered to the diseased portion of the lung.

One conventional method of introducing such agents into a patient'spulmonary system consists of interrupting ventilatory support andexposing the delicate lung tissues of the pulmonary system to higher,and potentially traumatizing, pressures needed for manually deliveringthe agents. When practicing many of the conventional chemotherapeutictechniques, the final distribution of the agents, throughout thepatient's pulmonary system, is generally non-uniform and typically“patchy”.

Another problem associated with the presently-practiced methods ofchemotherapeutic treatment of pulmonary-related diseases, conditionsand/or abnormalities is often encountered during intensive care lifesupport procedures. During such procedures, conventional gas ventilationis employed to maintain lung stability and to prevent lung collapse.However, the deleterious consequences of such life support proceduresoften precludes successful weaning from the particular life supportsystem back to pulmonary gas exchange. As such, the practice ofchemotherapeutic treatment, in conjunction with such conventional lifesupport systems and/or procedures, is severely hampered.

As exemplified above, there are significant problems which exist withconventional chemotherapeutic techniques of treating pulmonary-relateddiseases, conditions and/or abnormalities. Until this invention, theseproblems were unsolved.

SUMMARY OF THE INVENTION

The invention provides, in one embodiment, a hyperthermic treatment oflung cancer, which includes the steps of: temporarily filling with aliquid medium pre-selected pulmonary air passages adjoining pulmonarytissues containing malignant cells, circulating exogenously heatedliquid medium having a temperature in the range of from about 41° toabout 50° C. (preferably from about 42° to about 45° C.) through theliquid-filled pulmonary air passages for a predetermined period of time,and thereafter removing the liquid medium from the pulmonary airpassages of the patient. The liquid medium may be a perfluorocarbonliquid or physiological saline solution. Suitable perfluorocarbon liquidhaving the requisite physical and thermal properties are characterizedby an average molecular weight in the range of from about 350 to about560 and by having: a viscosity less than about 5 CP at 25° C., a densityless than about 2.0 g/cm³ at 25° C., a boiling point greater than about55° C., a vapor pressure in the range of from about 20 Torr to about 200Torr, and a Prandtl number less than about 10 at 25° C. Representativesof such perfluorocarbon liquids are FC-84, FC-72, RM-82, FC-75, RM-101,and perfluorodecalin. The preferred group of perfluorocarbon liquids ischaracterized by having an average molecular weight in the range of fromabout 420 to about 460, a vapor pressure less than about 100 Torr at 25°C., and a surface tension less than about 17 dynes/cm at 25° C.

The invention provides in another embodiment a hyperthermic treatment oflung cancer using ultrasound, including the steps of: temporarilyfilling with a liquid medium preselected pulmonary air passagesadjoining pulmonary tissues comprising malignant cells, heating theadjoining pulmonary tissues comprising the malignant cells to atemperature in the range of from about 41° to about 50° C. (preferablyfrom about 42° to about 45° C.) for a predetermined period of time bytransmitting ultrasound through the liquid-filled pulmonary airpassages, and thereafter removing the liquid medium from the pulmonaryair passages of the patient. Perfluorocarbon liquids having therequisite physical, thermal, and acoustic properties for this ultrasoundtreatment are characterized by an average molecular weight in the rangeof from about 400 to about 560. Such perfluorocarbon liquids are alsocharacterized by having: viscosity less than about 5 CP at 25° C.,density less than about 2.0 g/cm³ at 25° C., boiling point greater thanabout 75° C., vapor pressure in the range of from about 25 Torr to about100 Torr, surface tension below about 17 dynes/cm at 25° C., acousticimpedance in the range of from about 0.8 to about 1.6 MegaRayls at 37°C., and acoustic attenuation less than about 1.2 db/cm (at 1.0 MHz, 45°C., and acoustic intensity of about 3 W/cm²). The preferred group ofperfluorocarbon liquids for this purpose is characterized by an averagemolecular weight in the range of from about 420 to about 460, andrepresentative of these are FC-75, RM-101, and perfluorodecalin.Operable and preferred ultrasound frequency ranges are also disclosed,for use with different liquid-filled regions of the pulmonary airpassages. The ultrasound may be produced by a transducer disposed withinthe liquid-filled pulmonary air passages, or the transducer may bedisposed exogenous to the liquid-filled pulmonary air passages. Forexample, the ultrasound may be transmitted through an intercostal spaceof the patient, or it may be transmitted from an exposed surface of thelung into the volume of same during an intra-operative applicationinvolving an “acoustic window” into the lung created by surgical means.

In yet another embodiment, the invention provides liquid infusion andisolation catheters, intracavitary ultrasound applicators, andintercostal ultrasound applicators for practicing the disclosedconvection and/or ultrasound hyperthermia treatments of lung cancer.

In even another embodiment, the invention provides a means fordelivering biological agents directly to at least a portion of thepulmonary system via liquid-born agents which are either recirculated inand out of the pulmonary system (e.g., by liquid lavage or liquidventilation) or maintained static (i.e., non-recirculated) for extendedperiods of time. Breathable liquids are capable of providing,simultaneously, ventilation during drug delivery.

In still another embodiment, the invention provides a means to directlyaccess cardiac output for drug infusion of biological agents, whensystemic collapse precludes intravascular administration of such agents.

Other objects, aspects and embodiments of the invention will becomeapparent to those skilled in the art upon reading the following detaileddescription, when considered in conjunction with the accompanyingdrawings and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a representative liquid infusion and isolation catheteraccording to the invention;

FIG. 2 depicts a pair of representative intercostal ultrasoundapplicators;

FIG. 3 shows a representative intracavitary ultrasound applicator, andalso an optional cuff plug;

FIG. 4 shows the construction of a representative intracavitarytransducer assembly;

FIG. 5 shows another representative intracavitary ultrasound applicator;

FIG. 6 illustrates in greater detail the representative transducerassembly shown in FIG. 5;

FIG. 7 is a graph indicating the molecular weights of representativeperfluorocarbon liquids;

FIG. 8 is a graph indicating the surface tension (dynes/cm) ofrepresentative perfluorocarbon liquids;

FIG. 9 is a graph indicating the viscosity at 25° C. (CP) ofrepresentative perfluorocarbon liquids;

FIG. 10 is a graph indicating the density at 25° C. (g/cm³ ofrepresentative perfluorocarbon liquids;

FIG. 11 is a graph indicating the oxygen solubility (ml/100 ml) ofrepresentative perfluorocarbon liquids;

FIG. 12 is a graph indicating the boiling point (°C.) of representativeperfluorocarbon liquids;

FIG. 13 is a graph indicating the vapor pressure (Torr) ofrepresentative perfluorocarbon liquids;

FIG. 14 is a schematic depiction of a representative acoustical testsystem;

FIG. 15 is a graph indicating the velocity of sound (km/sec) inrepresentative perfluorocarbon liquids;

FIG. 16 is a graph indicating the acoustic impedance (MegaRayls) ofselected tissues and representative perfluorocarbon liquids at 37° C.;

FIG. 17 is a graph indicating the acoustic impedance (Rayls×106) ofrepresentative perfluorocarbon liquids as compared with water;

FIG. 18 is a graph indicating the relationship between perfluorocarboncavitation threshold (W/cm) and temperature (°C.) as a function of gassaturation;

FIG. 19 is a graph depicting acoustic losses in perfluorocarbon liquidsby plotting the relationship between perfluorocarbon acoustic intensity(W/cm²) and electrical intensity (W/cm²) at 1.0 MHz and 25° C.;

FIG. 20 is a graph depicting acoustic losses in perfluorocarbon liquidsby plotting the relationship between perfluorocarbon acoustic intensity(W/cm²) and electrical intensity (W/cm²) at 0.5 MHz and 25° C.;

FIG. 21 is a graph depicting acoustic losses in perfluorocarbon liquidsby plotting the relationship between perfluorocarbon acoustic intensity(W/cm²) and electric intensity (W/cm²) at 0.25 MHz and 25° C.;

FIG. 22 is a graph indicating the relationship between perfluorocarbonattenuation (dB/cm) and acoustic intensity (W/cm²) as functions oftemperature (25° or 45° C.) and frequency (MHz);

FIG. 23 is a graph indicating the relationship between acousticintensity (W/cm²) and electrical intensity (W/cm²) for FC-75 at 0.25 MHzand 45° C.;

FIG. 24 is a graph of acoustic intensity (W/cm² versus electricalintensity (W/cm²), indicating the attenuation range of variousperfluorocarbons at 1.0 MHz and 25° C.;

FIG. 25 is a graph of acoustic intensity (W/cm²) versus electricalintensity (W/cm²), indicating the attenuating effects of gas saturationin perfluorocarbon FC-75 at 1.0 MHz and 25° or 45° C.;

FIG. 26 is a graph of attenuation coefficient (dB/cm) versus frequency(MHz), showing in vitro perfluorocarbon-filled lung attenuation atvarious frequencies (MHz);

FIG. 27 is a graph of sound speed (m/sec) versus temperature (°C.),indicating the predominance of perfluorocarbon FC-75 in establishing thesound speed in liquid-filled lungs; these properties are compared withblood and muscle;

FIG. 28 is a graph of lung temperature (°C.) versus treatment time(min), demonstrating ultrasound hyperthermia of perfluorocarbon-filledpulmonary air passages;

FIG. 29 is a schematic diagram of the Large Animal Liquid VentilationSystem at Temple University;

FIG. 30 is a graph of tissue temperature (°C.) versus treatment time(min), demonstrating perfluorocarbon convection lung hyperthermia as afunction of tidal volume and liquid inspiration temperature;

FIG. 31 is a graphical depiction of ultrasound beam profiles fromrepresentative intracavitary applicators;

FIG. 32 is a graphical depiction of intracavitary phantom SAR profiles;

FIG. 33 is a graphical depiction of intracavitary applicator axial SARprofiles;

FIG. 34 is a schematic diagram of a representative liquid-filled lungconvection hyperthermia and liquid infusion system, wherein thefollowing abbreviations apply; IP, insp. pump; EP, exp. pump; ITP, insp.temp. probe; ETP, exp. temp. probe; IFM, insp. flow meter; EFM, exp.flow meter; IR, insp. reservoir; ER, exp. reservoir; CV, check valve;IRTP, insp. res. temp. probe; GCP, gas circular pump; and FS, freesurface;

FIG. 35 is a graphical depiction of cardiopulmonary responses to thepulmonary administration of acetylcholine;

FIG. 36 is a graphical depiction of cardiopulmonary responses to thepulmonary administration of epinephrine;

FIG. 37 is a graphical depiction of cardiovascular responses to thepulmonary administration of priscoline; and

FIG. 38 is a representative apparatus for producing a uniformlydispersed drug-containing phase within a continuous liquid deliveryphase.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides in one embodiment, a method of treating lungcancer by convection hyperthermia. Preselected pulmonary air passagesthat adjoin pulmonary tissues containing malignant cells are temporarilyfilled with a liquid medium such as physiological saline solution or,preferably, a perfluorocarbon liquid. By “pulmonary air passages” ismeant the pulmonary channels, spaces or volumes in the trachea, left andright bronchi, bronchioles, and alveoli of the lungs that are normallyoccupied by air. In the practice of the invention, only the pulmonaryair passages in contact with or near a patient's tumor site(s) aretypically filled with the liquid medium, and gaseous ventilation of theremaining pulmonary air passages is maintained. Depending on thelocation of the lung cancer, as determined by available diagnosticmethods, the fluid-filled pulmonary air passages may be localized in alung, lobe or lung segment, and/or the bronchial tree may be selectedfor localized filling with the liquid medium. Localized filling of thepulmonary air passages in such a preselected manner can be effected bymeans of the representative infusion catheters described below.Diagnostic ultrasonic imaging can be used to monitor the filling of thepulmonary air passages, if either physiological saline or aperfluorocarbon liquid serves as the liquid medium. During the fillingstep, the perfluorocarbon liquid is preferably degassed at least 50%,and is most preferably substantially (almost totally) degassed.

To effect the localized convection hyperthermia treatment, exogenouslyheated liquid medium having a temperature in the range of from about 41°to about 50° C., and preferably from about 42° to about 45° C., iscirculated through the liquid-filled pulmonary air passages for a periodof time that may be determined at the discretion of the attendingphysician. During, prior to or subsequent to this hyperthermictreatment, the malignant cells may be irradiated with ionizing radiationsuch as x-rays, electron beams, neutron beams, etc. To potentiate theeffects of such radiation treatments, the liquid medium in thefluid-filled pulmonary air spaces may be oxygenated. In treatments wherethe preselected pulmonary air passages are initially filled withsubstantially degassed perfluorocarbon liquid, exogenously heatedoxygenated perfluorocarbon liquid may be circulated into theliquid-filled pulmonary air passages after the filling process iscomplete, prior to and/or during irradiation of the malignant cells withthe ionizing radiation.

The circulating liquid medium may also contain a therapeutic agent suchas an anti-cancer drug (e.g., adriamycin), toxin, antibody-linkedradionuclide, etc. In treatments where the adjunctive use of suchwater-soluble therapeutic agents is desirable, the liquid medium may bean aqueous perfluorocarbon liquid emulsion.

After the hyperthermic treatment period, which as mentioned will vary ina patient-specific manner, depending partly upon the tumor location andany adjunctive therapies employed, the liquid medium is removed from thepulmonary air passages of the patient.

A preferred liquid medium for this convection hyperthermia treatment isa perfluorocarbon liquid of the general type used for lung ventilation.Suitable perfluorocarbon liquids having the requisite thermal as well asphysical properties for use in convection pulmonary hyperthermia includeperfluorocarbon liquids characterized by an average molecular weight, ofthe perfluorocarbon constituent(s), in the range of from about 350 toabout 560. Such perfluorocarbon liquids are alternatively characterizedby having a viscosity less than about 5 CP at 25° C., a density lessthan about 2.0 g/cm³ at 25° C., a boiling point greater than about 55°C., a vapor pressure greater than about 20 Torr but less than about 200Torr at 25° C., a surface tension less than about 17 dyne/cm at 25° C.,and a Prandtl number less than about 10 at 25° C. To provide someadjunctive respiratory support, and for use with radiation therapy, andto provide efficient lung filling in the degassed state, theperfluorocarbon liquid should also have an oxygen solubility greaterthan about 40 ml/100 ml. Representative perfluorocarbon liquids thatmeet the above criteria include FC-84, FC-72, RM-82, FC-75 (3M Company,Minneapolis, Minn.), RM-101 (MDI Corporation, Bridgeport, Conn.),dimethyladamantane (Sun Tech, Inc.), trimethylbicyclononane (Sun Tech,Inc.), and perfluorodecalin (Green Cross Corp., Japan). The preferredgroup of perfluorocarbon liquids, in terms of optimizing the operativecombination of physical and thermal properties, are characterized by anaverage molecular weight in the range of from about 400 to about 460.Such perfluorocarbon liquids are characterized by having a vaporpressure less than about 100 Torr. The most preferred perfluorocarbonliquids have an average molecular weight in the range from about 420 toabout 460, and representative of this group are FC-75, RM-101, andperfluorodecalin.

The invention also provides an ultrasonic hyperthermic treatment of lungcancer. In this embodiment, after the preselected pulmonary air passagesadjoining the patient's malignant cells are filled with the liquidmedium such that an adequate and appropriate acoustic transmission pathhas been established, the pulmonary tissues containing the malignantcells are heated to a temperature in the range of from about 41° toabout 50° C. by transmitting ultrasound through the liquid-filledpulmonary air passages. In a preferred embodiment, the ultrasound isproduced by an intracavitary transducer that is positioned within theliquid-filled pulmonary air passages. Alternatively, the transducer maybe located exogenous to the pulmonary air passages. For example, theultrasound can be transmitted through an intercostal space between theribs of the patient, or the transducer can be applied to the pulmonarypleura or lung surface overlying the fluid-filled passages, followingsurgical displacement of ribs or other interfering tissues.

In order to server as a suitable acoustical propagating medium in thisultrasonic hyperthermic treatment, the perfluorocarbon liquid shouldhave the following physical, thermal, and acoustical properties:viscosity less than about 5 CP at 25° C., density less than about 2.0g/cm³ at 25° C., boiling point greater than about 75° C., vapor pressuregreater than about 25 Torr and less than about 100 Torr, acousticimpedance between about 0.8 to about 1.6 MegaRayls at 37° C., andacoustic attenuation less than about 1.2 dB/cm (±20%) at 1.0 MHz, 45°C., and acoustic intensity of about 3 W/cm². The perfluorocarbon liquidis preferably also characterized by an oxygen solubility greater thanabout 40 ml/100 ml. Perfluorocarbon liquids having an average molecularweight in the range of from about 400 to about 500 generally satisfy theabove criteria, with the preferred group in terms of optimizing thethermal and acoustical properties having an average molecular weight inthe range of from about 400 to about 460, and most preferably in therange of about 420 to about 460. Representative of this most preferredgroup of perfluorocarbon liquids are FC-75, RM-101, andperfluorodecalin.

In treatments where the preselected liquid-filled pulmonary air spacesare localized in the bronchial tree, the ultrasound from anintracavitary transducer preferably has a frequency in the range of fromabout 250 KHz to about 3 MHz, and most preferably from about 500 KHz toabout 2 MHz. For peripheral lung treatments (i.e., in the membranousairways and alveoli of the lung), where the sound waves must necessarilytraverse many more liquid-tissue interfaces, a lower ultrasoundfrequency in the range of from about 250 KHz to about 1.5 MHz isnecessary when perfluorocarbon liquids serve as the liquid medium.Ultrasound frequencies in the latter range are also recommended when thetransducer is positioned exogenous to the lung.

The desired frequency within these ranges is established on the basis ofthe depth of heating sought. Lower frequencies are attenuated less and,therefore, are employed where deeper heating is preferred. Conversely,higher frequencies are more readily absorbed, and thus are moreappropriate for more superficial heating. Optimal treatments may includea combination of the following strategies. First, a single transducermay broadcast at more than one frequency to effect a desired heatingpattern. The changes in frequency in this case may be done by rapidincremental changes in frequency over a specified bandwidth usingfrequency modulation (FM) methods, or they may be done with serialchanges over time whereby sound (in FM mode or not) is generated inpredetermined frequency ranges for desired periods and then changed toother frequencies for periods of time. Second, multiple transducers(focused, diverging, or unfocused) may be employed to operate in tandemat similar or different frequencies (in FM mode or not) to effectdesired heating patterns.

Where physiological saline serves as the liquid propagating medium, theultrasound can be in the frequency range of from about 250 KHz to about3 MHz from intracavitary transducers, and in the range of from about 500KHz (preferably about 750 KHz) to about 3 MHz from exogenoustransducers.

While the perfluorocarbon liquid is preferably degassed during thefilling step, oxygenation of the liquid may be desirable (e.g., forradiation treatment or respiratory support) during the ultrasonichyperthermic treatment. However, in order to suppress cavitation, thedissolved gas content (including oxygen, air, nitrogen, carbon dioxideor other gases) of the perfluorocarbon liquid in the liquid-filledpulmonary air passages should be held at no more than about 75% ofsaturation for ultrasonic treatments in the 2-3 MHz range. No more thanabout 50% of saturation should be permitted for ultrasonic treatments inthe 250 KHz to 1.5 MHz range. The requisite dissolved gas content can bemaintained by circulating the perfluorocarbon liquid into and out of thelung during the treatment between the liquid-filled pulmonary airpassages and an extraneous source of gas-content processing, such as adegassing chamber.

The invention also provides liquid infusion catheters, intracavitaryultrasound applicators, and exogenous ultrasound transducers,representative embodiments of which are shown in FIGS. 1-5. Priorbifurcated bronchial catheters that have been used for delivering liquidinto a lung are not suitable for use in the subject convection andultrasonic hyperthermia treatments, for a number of reasons. First, thesubject treatments can be applied deeper in the lung than heretoforepossible, and prior commercial devices lack sufficient flexibility andlength to reach many of the segmented bronchi. In addition, theinflatable cuff material used in the prior devices tends to lose itsstructural integrity at the relatively high fluid temperatures involvedin the subject treatments. Furthermore, the prior devices are in generaltoo large in diameter to penetrate several of the pertinent segmentalbronchial passageways in the lungs, and they also provide noinstrumentation for monitoring local transient and steady statetemperature, and pressure, and are ill-suited for positionalinformation.

Referring initially to FIG. 1, a representative embodiment of thesubject liquid infusion and isolation catheter 20 is shown inconjunction with the pulmonary air passages 22 that lead to and ramifythroughout the lungs 24. More particularly, catheter 20 is shown passingthrough the larynx 26 and trachea 28 and into a bronchus 30 andassociated segmental bronchi 32.

Catheter 20 includes a flexible conduit 34 having a distal end 36 thatis positioned, in this instance, within segmented bronchus 32, and aproximal end 38 that is positioned outside (or exogenous to) thepatient. The representative embodiment shown in FIG. 1 has a pair ofinflatable cuffs 40 and 42 formed near the distal end 36 that are influid (liquid or gaseous) communication with corresponding channels 44and 46 that exit the conduit 34 near the proximal end 38. Also shown atthe proximal end 38, a liquid inlet/outlet connector 48 is in fluidcommunication through a liquid passageway 51 with an opening 50 at thedistal end 36 of conduit 34. A gas ventilation channel 52 also is formedin the conduit 34 to be in fluid communication with a ventilation port53 positioned so as to ventilate the bronchial tree. A pressure sensor54 and temperature sensor 56 are positioned near the distal end 36, andhave lead wires 58 and 60, respectively, passing through the conduit 34and exiting at the proximal end 38. The temperature sensor 56 may takethe form of a thermistor, thermocouple, resistance-based temperaturedevice, etc. Suitable pressure sensors 54 include: solid-statepiezoresistive diaphragm-based sensors, semiconductor strain gagesensors, etc.

The conduit 34 is typically formed from flexible plastics, such as aTeflon™, silicon rubber, polyurethanes, polyvinylchloride, Delrin™, oracetyl copolymers, or combinations thereof, having an outer thermalinsulation layer 64 formed, for example, of a closed-cell plastic orrubber, to reduce heat loss to the tissues in contact with it, betweenthe connector 48 and outlet 50 or at least the most proximal cuff 42.Alternatively, effective thermal insulation can be achieved by properselection of the catheter material itself and its channel wallthicknesses. To minimize diameter and maximize flexibility, the conduit34 is typically extruded to have the gas ventilation channel 52, thefluid channels 44 and 46, and the liquid passageway 51 integrally formedtherein. The above elements may alternatively be separately formed andbound in a common sheath (not shown), although this maydisadvantageously affect the diameter and flexibility of the conduit 20.

The cuffs 40 and 42 are preferably constructed of polyurethane or otherdistensible material that will maintain structural integrity whenstretched and yet not lose elasticity when subjected to high temperatureliquids. The cuffs 40 and 42 are concentrically formed about the conduit34 to be selectively inflated and deflated via liquids such asphysiological saline or perfluorocarbon liquids, or gas such as air,through the channels 44 and 46. A suitable connector 62, such as a Leurlock fitting, is located at the terminal end of each channel 44 and 46to provide attachment to a source of liquid or gas such as a lockablesyringe or a hand or mechanical pump. In the circumstance whereby liquidis the preferred cuff inflation fluid, it is likely that some liquidwill have been placed in the cuff prior to use, to insure a gas-freevolume inside the cuff. When inflated, the cuffs 40 and 42 bear againstthe encircling inner walls of the trachea 28, bronchus 30, and/or lobaror segmented bronchus 32 (depending upon the positioned location ofcatheter 20 in the pulmonary air passages 22), in order to locally sealthe lumen (3) of the airway(s) to prevent the passage of liquid and gasduring the hyperthermic treatment. Although a pair of cuffs 40 and 42are shown, one or both may be eliminated, e.g., if both lungs are to befilled with the fluid. Additional cuffs may also be used to provide therequisite sealing. The number of cuffs used will depend on where thehyperthermic treatment is being directed in the lung, the passageways tobe isolated and those to be kept gas ventilated, and the length of thecatheter 20. In this regard, the cuffs 40 and 42, when required, aresized according to their application, i.e., whether they will bepositioned in a large lobar bronchus (0.83 cm average diameter) or in asmaller segmental bronchus (0.56 cm average diameter). Cuffs sized todam the main bronchi (1.22 cm average diameter) and trachea (1.8 cmaverage diameter) can also be readily fabricated. The use of two cuffs40 and 42 in FIG. 1 is for illustration purposes only and is not meantto imply that the untreated distal pulmonary segments 32 are to beunventilated by gas. In use, the catheter configuration(s) will beselected to reflect the requirement to gas ventilate untreated,air-filled portions of the lung.

The gas ventilation channel 52 is used to provide respiratory gasexchange to the portions of the lungs 24 not sealed off by the cuffs 40and 42 or filled with the liquid. The channel 52 is preferably coupledto an appropriate machine, such as a mechanical ventilator, to supplygas through the port 53 formed in the wall of the conduit 34. In theabsence of such a connection air ventilation may occur by the gas beingdrawn into channel 52 from room air by the natural respiratory motion ofthe lung.

The liquid connector 48 is attached to a liquid infusion system, such asdescribed below. Briefly, such a system provides liquid for the desiredtreatment at a controlled but variable tidal volume and frequency, andat a controlled temperature and gas content. The pressure sensor 54 andthe temperature sensor 56 positioned at the delivery end 36 permitmonitoring of the temperature and pressure of the liquid within theliquid filled air passages. Additional sensors may be positioned at anypoint along the conduit 34 to permit comparative measurements and topermit flow rate information in the catheter to be obtained from dynamicmeasurements.

In use, the catheter 20 may be fitted with a rod (not shown) formed ofbendable material, such as aluminum, that is bent, prior to insertion inmost cases, to a configuration designed to guide the catheter 20 throughthe trachea 28 to the desired location in the pulmonary air passageways20. A fiber-optic assembly may be used either alone or in conjunctionwith the rod to provide visual confirmation of the positioning of thecatheter 10. Such a fiber-optic assembly, including an optical fiberhaving a lens, may be integrated into or associated with the catheter20, and coupled to a light source and an eyepiece to permit observationvia video camera, still photographs, or the eye. A fiber-opticbronchoscope may be alternatively inserted through liquid passageway 51for the same purpose. To assist in measuring distances to various partsof the lung, the outer surface of catheter 20 may be provided withdistance indicator marks in spaced array.

Once the catheter 20 is in position, the various connectors at theproximal end are connected to the appropriate machines and monitoringdevices. For instance, the liquid inlet/outlet connector 48 is attachedto a liquid infusion system, and the fluid line connectors 62 areattached to suitable sources of liquid or gas. The cuffs 40 and 42 areinflated as necessary to seal off the pulmonary air passages adjoiningthe cancer cells while maintaining gas communication to untreated lungvolume. The gas ventilation channel 52 is hooked to a mechanicalventilator and a suitable gas mixture is supplied through the port 53 tothe unaffected air passageways. With temperature and pressure beingmonitored, liquid from the infusion system is supplied through theliquid passageway 51 to the, in this instance, bronchiole 32 at acontrolled frequency and tidal volume (indicated by arrow 51). Followingthe hyperthermic treatment, the liquid can be removed from the pulmonarypassages 20 by suction, by gravity (i.e., placing the patient tiltedwith the head down in the so-called “Trendelenburg” posture), and byevaporation.

The liquid infusion and isolation catheter 20 may also be used inconjunction with external intercostal ultrasound applicators to providethe means for liquid filling and to provide additional heating and/orcooling to the tumor site. For instance, as shown in FIG. 2, a pair ofintercostal applicators 66 and 68 are placed externally on the patientto direct sound waves between the ribs 70 and into the peripheralportions and bronchial spaces of the lung 24. These ultrasound powerapplicators 66 and 68 are composed of long aspect-ratio rectangulartransducers 74, operated either singly or as a synchronous orasynchronous pairs. These applicators 66 and 68 can have flat (planewave), broad-band unfocused transducers 74 or may have curved, focusedtransducers. Ideally these will be operated in the range from 250 KHz to1 MHz.

Such applicators 66 and 68 can be used in conjunction with a liquidinfusion and isolation catheter 20 to apply heat both convectively andultrasonically to a specific portion of the lung 24. Although it wouldappear that a venetian blind or striped pattern of heating would resultfrom this arrangement, it should be noted that the targeted tissue canbe “scanned” up and down in front of the transducer array by a cyclicvariation of the inflation pressure of the lung 24. This inducedvariation may be large or small, according to the motion desired.Likewise, the overall position of the tumor to be treated may be locatedwith respect to the applicators 66 and 68 by virtue of inflation ordeflation of the lung 24. Also, the respiratory motion normally presentin the lung 24 may be suppressed by imposing a constant liquid infusionpressure at the desired level. Although not shown, it is to beunderstood that the applicators 66 and 68 may be in fixed positionrelative to each other, such as by mounting to a jig or frame.

Although not shown in this view, a transducer can alternatively beapplied directly to the body of the lung following surgical resection ofa rib or other interfering tissues. The transducer for this applicationwill typically be supplied with a bolus of degassed coupling liquid,also serving the function of cooling the transducer and tissue surfaces.

Another method of providing ultrasound hyperthermia is to place anultrasound applicator within the fluid-filled pulmonary air passage nearthe tumor to be treated. FIG. 3 shows a representative embodiment ofsuch an intracavitary applicator 76 for delivering an ultrasoundtransducer 78 to the treatment site. To facilitate the description, thereference numbers used in FIG. 1 are correspondingly employed in FIG. 3(and in FIG. 4, described below). The intracavitary applicator 76 ofFIG. 3 includes a conduit 80 having a distal end 82 positionable withinthe pulmonary air passages 22 and a proximal end 84 that remains outsidethe thoracic air passage 22. The conduit 80 encases a ventilationpassageway 86 passing through the transducer 78 in fluid communicationwith the pulmonary air passages 22 through a distal opening 88. Thepassageway 86 terminates at the proximal end 84 of the conduit 80 with acoupling 90 for attachment to a respirator (not shown). The conduit 80also houses a liquid inlet port 92, typically positioned distal to thetransducer 78, and a liquid return port 94 positioned, in this instance,proximal to the transducer 78. The liquid inlet port 92 is in fluidcommunication with a liquid inlet coupler 96, and a liquid return port94 is in fluid communication with a liquid return coupler 98, bothcouplers 96 and 98 being located at the proximal end 84 of the conduit80. Formed concentrically about the ventilation passageway 86 andpositioned distal to the transducer 78 and liquid ports 92 and 94 is aninflatable cuff 100. A fluid line coupling 102 is in fluid communicationwith the cuff 100, for connecting the cuff 100 to a suitable source ofpressurized liquid or gas (e.g., air). Power cables 104 pass through theconduit 80 to provide high frequency electrical power to the transducer78.

This conduit 80 is constructed with similar materials and by similarmethods as the liquid infusion catheter 20 described above. Here, inFIG. 3, the transducer assembly 78 is positioned concentrically aroundthe ventilation passageway 86. In this manner, the distal cuff 100, wheninflated, serves to dam the proximal pulmonary passages 30′. The distalcuff 100 also anchors the distal end 82 of the conduit 80, and therebypermits the transducer 78 to be manipulated into position in the centerof the bronchus 30 (or trachea 28) to avoid contact with the bronchuswall 106 and the tumor 108. The cuff 100 is otherwise substantially thesame as the cuffs 40 and 42 described above with respect to FIG. 1. Whenthe cuff 100 is inflated, it seals off the bronchus 30 so that adegassed liquid propagating medium 110 can be supplied to and fill thebronchus 30 through the liquid inlet port 92, to provide acousticcoupling and secondarily to cool the transducer assembly 78. Circulationof the liquid 110 may be accomplished by circulating liquid from thebronchus 30 through the liquid return port 94 to a liquid supply system,such as described below.

In order to prevent filling of the other lung, if that is desirable, anoptional cuff plug 112, which is independent of the intracavitarytransducer and its support shaft and conduit 80, is inserted within theother bronchus 30′, and its degree of distension is controlled withpressurized liquid or gas supplied through a line 114. Respiration isaccomplished through the one lung by supplying air through theventilation passageway 86. Although not shown, it is to be understoodthat the cuff assembly 112 and 114 may, and preferably should, besupplied with a separate ventilation passageway (not shown) in order toventilate the pulmonary air passage 32 distal to cuff plug 112. Pressureand temperature sensors (not shown) may also be disposed and used asdesired, such as described above with respect to FIG. 1. Installation ofthe intracavitary applicator 76 can be accomplished substantially thesame way as described above with respect to the liquid infusion andisolation catheter 20. Positioning of the transducer 78 with respect tothe tumor 108 is accomplished by rotating the conduit 80 as shown by therotational arrow 116.

The construction of such a representative intracavitary transducerassembly 78 is shown in greater detail in FIG. 4. Here, one approach toproviding selective directional heating patterns is illustrated. FIG. 4shows a thin-walled piezoelectric ceramic cylinder 180 that islongitudinally and circumferentially sectioned into four separate powertransducers, with transducers 120 and 122 formed to have an arcuatecross-sectional shape of approximately 120°, as indicated by angle θ;and with transducers 124 and 126 formed to have an arcuatecross-sectional shape with an included angle of approximately 240°, asrepresented by angle φ. Leads 128 supply power to the transducers, andthe ventilation passageway 86 is shown, in this instance, passingcoaxially through the cylinder 180. This multiple-transducer approachprovides flexible heating patterns. For instance, with transducers 120and 122 driven in parallel, a 120° pattern can be achieved. Similarly,with transducers 124 and 126 driven in parallel, a 240° heating patterncan be achieved. Finally, with all of the transducers being driventogether, a full 360° of heating can be achieved along the length of thecylinder 180. Of course, full 360° heating patterns may also be achievedby cylindrical piezoelectric cylinders that are not sectioned.

Although the transducer assembly 78 is shown mounted coaxial with theconduit 80, it is to be understood that other positions and transducerconfigurations can be used. For instance, transducers formed of flatplates may be associated with or placed adjacent to the conduit 80 toradiate sound waves in one or more directions. Likewise, the transducers124 and 126 may be eliminated to leave only the transducers 120 and 122mounted adjacent the conduit 80.

FIG. 5 illustrates yet another representative embodiment of anintracavitary ultrasound applicator 130, in which a transducer assembly132 positioned within a self-contained liquid-filled sac 134 foracoustic coupling and cooling. This applicator 130 includes a conduit136 having a distal end 142 positioned within the bronchus 30 and aproximal end 144 positioned outside of the patient's body. A ventilationpassageway 138 is formed within or associated with the conduit 130having a ventilation port 140 formed approximately midway down theconduit 136 and an air line coupling 146 located at the proximal end 144for attachment to a respirator (not shown). While not shown in thisview, a ventilation passageway can also be provided to the distal end142 if desired.

The conduit 136 also houses one or more liquid passageways that supplyliquid from a liquid inlet coupling 148 to the distensible sac 134, andcirculate liquid back to a liquid outlet coupling 150. The couplings 148and 150 may be connected to a self-contained liquid supply system or alarger system containing a separate power supply circuitry and fluidflow module that circulates a degassed liquid at a controlledtemperature for cooling the transducer assembly 132 and providing anacoustic coupling between the transducer assembly 132 and the pulmonarytissues and tumor 152. It is also possible to derive thecoupling/cooling fluid from the liquid infusion system that suppliesliquids to the lung. The sac 134 is constructed of a thin, pliablematerial, such as polyurethane, that readily conforms to the shape of anabutting pulmonary tissue or tumor to facilitate heating of the tumor. Afiber-optic assembly is shown as part of the applicator 130 having oneor more optical fibers (not shown) passing through the liquid sac 134and the transducer 132. The fiber-optic assembly includes a lens 156positioned on the distal end 142 of the conduit 136, an optical coupler158 at the proximal end 144 to facilitate viewing through the lens 156as previously described, and a light source that is supplied throughcables 160 that also include power cables for the transducer assembly132. A cuff 162 typically is formed on the conduit 80 distal to thetransducer assembly 132, to be inflated and deflated through a cufffluid line coupling 164 that is connected to a source of pressurizedliquid or gas. This cuff 162 serves primarily an anchoring function, toassist and maintain acoustical positioning of the transducer 132 andliquid-filled sac 134 at the tumor site 152.

Both of the intracavitary applicators 76 and 130 described above can bepositioned in the bronchial tree by first locating the tumor target viaa flexible bronchoscope that indexes the lengths of the passageways andthe position of the tumor. The applicator is then guided down theairways with the aid of a bendable rod, as described above. Such a rodis first bent slightly and then fed down one of the inner passageways ofthe applicator. The bend of the rod is sufficient to bend the distal endof the applicator in the desired direction. Supplementing this steeringapproach is a system of fiduciary marks taken from or correlated withthe bronchoscope traversal that establishes the length required todescend down the airways. Finally, the fiber-optic assembly 154 can beused alone or in conjunction with the rod to accurately position thetransducer assembly adjacent to the tumor to be treated.

The intracavitary applicator 130 may also be configured for hyperthermictreatment in other body cavities, e.g., the mouth, esophagus, uterus, orrectum, in which case a cuff may be provided for auxiliary anchoringpurposes.

FIG. 6 illustrates in greater detail a representative transducerassembly 132 for use in conjunction with the distensibleacoustic-coupling sac 134. Here, the conduit 136 is shown in crosssection having a liquid inlet passageway 166 centrally positioned withina concentric liquid return passageway 168. The liquid 170 passes througha manifold 172 into the lumen of the sac 134 to distend the sac 134 andcirculate around the transducers 174. The liquid 170 then passes throughthe manifold 172 and into the return passageway 168. The circulation ofthe liquid 170, which is normally degassed water, aids in cooling thetransducers 174 and provides an acoustic coupling for the ultrasoundwaves 176. Although not shown, it is to be understood that cuff fluidlines and the fiber-optic assembly lines can be constructed to passaxially through the sac 134 and the transducers 174 to distal positionsalong the conduit 136.

Another embodiment of the invention provides a means for deliveringbiological agents, through the pulmonary air passages of a patient, fortreating, controlling and/or diagnosing pulmonary and/or systemic,diseases, conditions and/or abnormalities. In this embodiment of theinvention, the biological agents are delivered into at least a portionof the pulmonary system via the implementation of liquidlavage/ventilation of at least a portion of the patient's pulmonary airpassages. Specifically, in this embodiment of the invention, biologicalagents are delivered into at least a portion of the patient's pulmonarysystem via liquid-born agents which are either recirculated in and outof the preselected portion of the pulmonary air passages in a liquidlavage fashion or maintained static (non-recirculated) for extendedperiods of time. If breathable liquids are used, pulmonary delivery ofbiological agents can be performed with simultaneous pulmonaryventilation.

As used herein, the phrase “biological agents” refers not only tophysiologically-active agents (e.g., chemotherapeutic agents), but alsoto physiologically-inert agents (e.g., diagnostic agents).

As used herein, the phrases “liquid lavage”, “liquid ventilation”,and/or “liquid lavage/ventilation” individually and collectively referto gravity-assisted and/or mechanically-assisted passing of liquidmediums through at least a portion of a patient's pulmonary airpassages. The liquid mediums being passed therethrough need not,necessarily be “breathable” (e.g., in those instances when a liquidlavage process is employed solely for washing/rinsing a portion of thelungs). However, when employed in liquid ventilation, it is preferablethat the liquids have the ability of gas exchange.

This embodiment of the invention, pertaining to the pulmonaryadministration of biological agents, provides a method for treating,controlling and/or diagnosing a patient's pulmonary-related diseases,conditions and/or abnormalities. This new method is especially usefulwhen treating, controlling and/or diagnosing conditions wherein blood ispreferentially shunted away from diseased pulmonary regions and,thereby, systemically delivered agents are at least partially precludedfrom reaching these regions. This embodiment is also useful as a meansfor introducing agents such as surfactants, steroids, antibiotic agents,chemotherapeutic agents, chemotactic agents, diagnostic agents, and thelike, primarily, if not exclusively, into the pulmonary system, whensystemic absorption of such agents is undesirable.

The implementation of liquid lavage/ventilation techniques, as a vehiclefor delivering biological agents to at least a portion of a patient'spulmonary system, is of particular importance for many reasons. Examplesof some of the advantages associated with the pulmonary administrationof biological agents includes, but are not limited to, the following:(a) it results in the homogenous delivery of the agents throughout thepulmonary system for treating, controlling and/or diagnosing diffusediseases, conditions and/or abnormalities, while simultaneouslysupporting gas exchange, if desired; and/or (2) it can be employed toselectively deliver biological agents to desired areas of the pulmonarysystem for treating controlling and/or diagnosing local diseases,conditions and/or abnormalities. In each of the aforementionedinstances, the process of the selective pulmonary administration ofbiological agents minimizes normal, healthy, delicate pulmonary tissuesfrom being exposed to toxic agents, such as is often encountered duringconventional systemic chemotherapeutic and/or diagnostic techniques.

When practicing the embodiment pertaining to the pulmonaryadministration of biological agents, the biologically active agents,passing through at least a portion of the patient's pulmonary airpassages, can react with, and/or diagnose, the patient's biologicalsystem in a number of ways. For example, the biological agentsintroduced in accordance with the invention, by pulmonaryadministration, may be used in the following ways: (a) to react directlyon and/or diagnose the patient's pulmonary system, (b) to react onand/or diagnose both the patient's pulmonary and systemic system, and/or(c) to differentially react on and/or diagnose specified regions of thepatient's pulmonary system.

Through research, it was discovered that there are many advantages ofdelivering biological agents directly to the surface of the pulmonaryair passages (e.g. lungs) via liquid lavage/ventilation. Some of themore important advantages include, but are not limited to, thefollowing:

1. The delivery of the desired biological agents directly through apatient's pulmonary air passages is enhanced by several physiologicalprinciples, such as, for example, (a) the large exchange surface area ofthe lung (i.e., from about 50 to about 100 m²), (b) the entire cardiacoutput passes through the pulmonary capillary bed, (c) the thin barrier(i.e., alveolar wall thickness) and the short diffusion distancesenhances absorption of the agent, and (d) the uniform distribution oflow surface tension liquids throughout the pulmonary system.

2. In many cases, the action of the biological agents (e.g., surfactantsto lower pulmonary surface tension, bronchodilators to relax airwaysmooth muscle, pulmonary vasodilators to increase pulmonary blood flow,steroids for lung inflammation, chemotactic agents, chemotherapeuticagents and/or diagnostic agents for lung cancer, and the like) areexclusively directed to a portion of the patient's pulmonary airpassages (e.g., lungs) and would be undesirable in the rest of the body.

3. In diseases and/or abnormal lungs, a common problem is poordistribution of pulmonary blood flow and ventilation. This problem isobviated in the liquid-filled lung, in that liquid and blood flow areuniformly distributed and matched. This physiological principle enablesefficient exchange of biological agents into a lung where exchange wouldotherwise be impossible.

4. Liquids can be selectively directed to specific regions of thepatient's pulmonary air passages by a number of different conventionalmeans, such as a bronchoscope, a conventional catheter or even aspecialized catheter, similar to that employed in the hyperthermiatreatment mentioned earlier. This capability of selectively directingliquids comprising biological agents would be particularly useful whenonly a specific region of the patient's pulmonary system requiresdelivery of such agents (e.g., chemotherapeutic cancer drugs which maybe harmful to normal, healthy lung and body tissues in highconcentrations and agents which facilitate pulmonary debridement).

5. In the case of systemic vascular compromise or shock, intravascularadministration of agents is ineffective under conventional practices.However, the passage of the necessary biological agents through at leasta portion of the patient's pulmonary air passages by liquidlavage/ventilation techniques provides a direct route for agentadministration.

When practicing the embodiment of the invention pertaining to thepulmonary administration of biological agents, the selected liquid isaugmented with the selected biological agents. These agents can bepresent in the liquid medium in any suitable form (e.g., bulk form, asuspension, a dispersion, a liquid form, an emulsion form, encapsulizedand the like and/or combinations thereof). The particular form of thebiological agent, will depend upon many different variables (e.g., thespecific agent being used, the area being treated and/or diagnosed, thecondition and/or abnormality being treated, controlled and/or diagnosed,the parameters under which the liquid lavage/ventilation process isperformed, etc.).

Moreover, the selected biological agents can be incorporated into theliquid medium by any suitable technique. Examples of suitableincorporation techniques include, but are not limited to, injection,blending, dissolving, employing conventional incorporation proceduresand incorporation of specific incorporation procedures (see, e.g., FIG.38).

Any suitable biological agent can be employed when practicing thisembodiment of the invention. Examples of suitable biological agentsinclude, but are not limited to, anti-cancer agents, vasoconstrictors,vasodilators, bronchoconstrictors, bronchodilators, surfactants,steroids, antibiotic agents, chemotactic agents, toxins, antibody-linkedradionuclides, diagnostic agents, contrast agents, and the like, and/orcombinations thereof.

When employing vasoconstrictors, vasodilators, bronchoconstrictorsand/or bronchodilators (e.g., epinephrine, acetylcholine, priscoline andsodium nitroprusside), they can be used in any suitable amount necessaryto achieve the desired results, in view of the specific conditions,diseases and/or abnormalities present. For example, the amount of thesebiological agents can range from between about 0.001 to about 10.0 mgfor each kilogram of body weight of the patient whose physiologicalconditions, diseases and/or abnormalities are being controlled,diagnosed and/or treated in accordance with this embodiment of theinvention. In another instance, it may be desirable to have the amountof these biological agents range from between about 0.004 to about 7.0mg/kg, or from between about 0.007 to about 4.0 mg/kg, or from betweenabout 0.01 to about 1.0 mg/kg.

As indicated above, the amount of biological agent employed depends, inpart, on the specific set of circumstances revolving around eachindividual case.

In addition to the above, this embodiment is particularly useful fordelivering anti-cancer drugs (e.g., adriamycin), toxins, antibody-linkedradionuclides, and the like and/or combinations thereof, to at least aportion of the patient's pulmonary system by being passed through thepatient's pulmonary air passages.

Any suitable liquid can be used as the liquid carrier when practicingthe embodiment pertaining to the pulmonary administration of biologicalagents. As stated earlier, depending upon the specific circumstances,the liquid carrier need not be breathable. In most instances, however,the liquid carriers employed are breathable.

Particularly useful breathable liquids which can be used as the liquidcarrier include, but are not limited to, perfluorochemicals, saline,silicone and vegetable oils, and the like. Of the aforementioned liquidsperfluorochemicals (e.g., perfluorocarbon) liquids are presentlypreferred.

Some of the reasons for preferring perfluorochemicals include, but arenot limited to, (a) they have a high solubility for respiratory gases,thereby being able to maintain ventilation during therapeutic and/ordiagnostic procedures; (b) they have a low surface tension whichfacilitates the uniform distribution of the liquids and the biologicalagents throughout the pulmonary system; and/or (c) they are generallybiologically inert, thus preventing possible side-effects due to theliquid carrier and the biological agent interacting. It should be noted,however, that other liquids can be preferred over perfluorochemicals,depending upon the specific circumstances and the desired results.

There are a number of clinical conditions when liquid lavage (washing)of the pulmonary system is necessary to debride the alveolar surfaces ofunwanted secretions, particles, toxins, etc. (e.g., alveolarproteinosis, cystic fibrosis, aspiration syndromes, and the like).Conventional lavage procedures generally employ the use of isotonicsaline as the washing media since it is relatively non-damaging to thealveolar surface. However, because saline does not carry a substantialamount of oxygen to support respiration, only one lung can be washed ata time. The other lung is maintained with 100% oxygen. This imbalanceusually results in hypoxia during and after conventional the lavageprocedures.

In several research reports, it has been documented that it is possibleto wash both lungs, simultaneously, if a breathable liquid (e.g.,perfluorocarbon) is employed as the washing media. In view of theembodiment of the present invention pertaining to the pulmonaryadministration of biological agents, an extension of the concept whichemploys breathable liquids as the washing media, in a liquid lavageprocedure, is to augment the breathable liquid with an effective solventappropriate for the particular injury to the patient's pulmonary airpassages. For example in the case of Adult Respiratory Distress Syndrome(also referred to herein as “ARDS”), the breathable liquid may contain asuspension of antiproteases to more effectively perform the followingfunctions: (a) inhibit protein leakage, (b) wash out alveolar debris and(c) maintain gas exchange. Furthermore, in the case of aspirationsyndromes, the breathable liquid may contain an agent to neutralize orbuffer the action of the aspirant on the lung surface. For example, ifthe aspirant is of an acidic nature (e.g., gastric contents), thebreathable liquid may be buffered with bicarbonate to balance the pH andminimize lung epithelial damage.

When practicing the embodiment of the invention, wherein the biologicalagents are introduced via a liquid lavage procedure, the liquid carrier(augmented with the desired biological agents, whether in bulk,suspension, dispersion, emulsion and/or encapsulization form) can beplaced in an inspiratory reservoir (R_(I)). This inspiratory reservoiris generally suspended above the patient and is in open communicationwith at least a portion of the patient's pulmonary air passages. Forexample, two ends of a Y-piece can be used to interconnect the R_(I)with the patient's endotracheal tube.

Gas ventilation is generally interrupted when instilling the liquidfunctional residual capacity from the R_(I). This residual capacity maycontain at least a portion of the desired biological agents. Gas and/orliquid ventilation is then resumed and/or initiated depending uponwhether the process is (a) a total or partial ventilation, (b) a totalor partial lavage with breathable liquid, or (c) a total or partiallavage with a non-breathable liquid.

After the resumption and/or initiation of gas and/or liquid ventilation,tidal volumes of a liquid washing medium are passed through thepatient's pulmonary air passages. These tidal volumes of liquid mediummay contain at least a portion of the desired biological agents.

In liquid lavage techniques, the tidal volumes of liquid can be passedthrough the desired portion of the patient's pulmonary air passages viagravity assistance, mechanical assistance or a combination of both.Similarly during liquid lavage techniques, the liquids can be removedfrom pulmonary air passages via gravity and/or mechanical assistance. Ifa Y-piece is employed as described above, the expired liquids can passthrough its remaining port and be deposited into an expiratoryreservoir.

Although the residual capacity of liquid remains in the pulmonary airpassages throughout the entire lavage/ventilation procedure, each tidalvolume of liquid is held within the patient's lungs for a period of timenecessary to achieve the desired results, while maintaining thenecessary exchange of gases, if necessary. For example, the liquid canbe retained in the patient's pulmonary system for a period of timeranging from between about 60 seconds to about 1 second. In mostinstances, however, it will not be necessary to retain the tidal volumeliquid in the patient's pulmonary system for more than about 30 seconds.

Similarly, the frequency of the tidal volumes of liquid also dependsupon the specific results desired.

On the other hand, when practicing the embodiment of the invention,wherein biological agents are introduced via a liquid ventilationprocedure, the liquid ventilation process can also be achieved using agravity-assisted system and/or a mechanically-assisted system. In thisprocedure, breathable liquid is generally oxygenated to maintain thearterial oxygen tension (P_(a)O₂) constant; and carbon dioxide (CO₂) isgenerally scrubbed from the system. Thereafter, the pO₂ and pCO₂ of theliquid are typically sampled, analyzed and/or controlled during theventilation process to ensure constant inspired gas tensions and drugdelivery levels. It should be noted that the augmentation of the liquidcarrier with the biological agents can be performed either before,during and/or after the liquid is oxygenated.

Once the patient is connected to the liquid ventilation system which isbeing used as the vehicle for the pulmonary delivery of biologicalagents, tidal volume (V_(T)) and functional residual capacity (FRC) ispreferably monitored and/or controlled. Generally, ventilation schemeswill be initially adjusted for effective carbon dioxide elimination andmaintenance of physiological arterial CO₂ tension (P_(a)CO₂). Inaddition to the above, breathing frequency (f), V_(T) and FRC are alsogenerally monitored and/or adjusted to obtain physiological P_(a)O₂ andP_(a)CO₂.

Regardless of whether a liquid lavage and/or ventilation technique isemployed as the vehicle for carrying biological agents to the patient'spulmonary system via the patient's pulmonary air passages, heart rate,arterial pressure, hemoglobin-oxygen saturation, arterial blood gastensions, and/or pulmonary function are generally evaluated before andduring the process.

When practicing the embodiment of the invention pertaining to thepulmonary administration of biological agents via liquidlavage/ventilation, the liquid medium can be heated or cooled totemperatures above or below the patient's normal body temperaturedepending, again, on the specific conditions and/or desired results. Forexample, in addition to the liquid medium being at our about thepatient's normal body temperature, it can also be greater or less thanthat temperature.

For example, the temperature of the liquid medium, either before and/orduring the liquid lavage/ventilation process, can range from betweenabout the normal body temperature of the patient whose physiologicalconditions, diseases and/or abnormalities are being diagnosed,controlled and/or treated to about 20% above the patient's normal bodytemperature. Generally, if such a hyperthermic treatment is desired, thetemperature of the liquid medium can range from about the patient'snormal body temperature to about 15% greater than the patient's normalbody temperature, or from about the patient's normal body temperature toa temperature about 10% greater than the patient's normal bodytemperature, or from about the patient's normal body temperature to atemperature about 5% greater than the patient's normal body temperature,or from about the patient's normal body temperature to a temperatureabout 1% greater than the patient's normal body temperature. In eachinstance, the liquid medium's temperature will depend upon the specificcircumstances present and the results desired.

Moreover, the temperature of the liquid medium, either before and/orduring the liquid lavage/ventilation process, can range from betweenabout the normal body temperature of the patient whose physiologicalconditions, diseases and/or abnormalities are being diagnosed,controlled and/or treated to about 20% below the patient's normal bodytemperature. Generally, if such a hypothermic treatment is desired, thetemperature of the liquid medium can range from about the patient'snormal body temperature to about 15% less than the patient's normal bodytemperature, or from about the patient's normal body temperature to atemperature about 10% less than the patient's normal body temperature,or from about the patient's normal body temperature to a temperatureabout 5% less than the patient's normal body temperature, or from aboutthe patient's normal body temperature to a temperature about 1% lessthan the patient's normal body temperature. As above, the temperature ofthe liquid medium will depend upon the specific set of circumstancespresent and the results desired.

In addition to the above, it is also within the scope of this inventionfor the liquid medium's temperature, either before and/or during theliquid lavage/ventilation, to range from between about 10% below toabout 10% above the normal body temperature of the patient whosephysiological conditions, diseases and/or abnormalities are beingdiagnosed, controlled and/or treated. In other instances, however, itmay be desirable to have the temperature of the liquid medium range frombetween about 5% below to about 5% above the patient's normal bodytemperature, or from between about 3% below to about 3% above thepatient's normal body temperature, or from between about 1% below toabout 1% above the patient's normal body temperature.

When practicing the embodiment pertaining to the pulmonary delivery ofbiological agents, the particular temperature range of the liquidmedium, either before and/or during the liquid lavage/ventilation, willdepend upon the desired results and specific circumstances of eachindividual implementation.

As stated earlier, the embodiment of the invention, pertaining to thepulmonary administration of biological agents, is especially useful fortreating certain types of lung cancer. The phrase “lung cancer” as usedherein, generally refers to tumors arising in major airways andpulmonary parenchyma.

Therapeutic treatment of lung cancer with chemotherapeutic agents (e.g.,adriamycin, toxins, antibody-linked nuclides, etc.) may have devastatingeffects on systemic tissues when delivered at the high levels which aregenerally necessary for the treatment of many types of lung cancer.

On the other hand, the embodiment of the present invention, whichemploys liquid lavage/ventilation techniques for the pulmonaryadministration of biological agents, provides a successful means fordelivering therapeutically high levels of anti-cancer agents to the lungsurface (cancer site) relative to the systemic tissues, thereforeminimizing adverse side effects.

Another pulmonary abnormality, which can be chemotherapeutically treatedwith the embodiment of the present invention pertaining to the pulmonaryadministration of biological agents, is respiratory distress syndrome.Respiratory distress syndrome is characterized in both neonate andadults by their inability to effectively exchange oxygen and carbondioxide as a result of lung immaturity (infants only), damage, or acombination of both.

Because breathable liquids, such as perfluorocarbons, have low surfacetensions and high solubilities for respiratory gases, when practicingthe present invention, such liquids can be used to homogeneously expandthe lung with low pressures, while simultaneously supporting gasexchange and delivering biological agents to regions of the lung whichare generally not accessible by systemic circulation. In comparison toexisting conventional procedures for treating respiratory distresssyndrome, the approach employed when practicing the present inventionsignificantly reduces the risk of pulmonary damage.

Particular therapeutic agents which would be applicable in the treatmentof respiratory distress syndrome (RDS) include, but are not limited to:exogenous surfactants, antibiotics, steroids, antioxidants,antiproteases, bicarbonate and the like. While all of these agents haveproven clinical applicability for treatment of RDS, they havesignificant limitations associated with their conventional means ofdelivery. However, the pulmonary administration of these agents, inaccordance with the practices of the present invention, (a) provides ameans for overcoming most of the limitations encountered by conventionaladministration techniques and (b) effectively delivers theaforementioned agents to the injured/abnormal regions of the patient'spulmonary system. Moreover, due to the evaporative characteristics ofmany breathable liquids, practicing the present invention in this mannerprovides a means for assured deposition of these agents onto the lungsurface, without residual interference due to the liquid carrier.

Yet another process, wherein the embodiment of the invention pertainingto the pulmonary administration of biological agents can be employed, isin Airway Smooth Muscle (ASM) Control. In addition to controllingpulmonary vascular smooth muscle for pulmonary circulation, bypracticing the present invention, it is now possible to augment certainbreathable liquids (e.g., perfluorocarbons) with therapeutic agentswhich control ASM and, therefore, airway resistance to flow.

In the case of severe asthma, the ASM contracts such that respiration isimpeded and hypoxia and hypercapnia generally results. We havedemonstrated that the addition of a ASM agonist and antagonist to abreathable liquid can significantly alter ASM tone and, subsequently,affect ventilating pressures. Specifically, in Example 12 of thisinvention (infra), acetylcholine was injected into a perfluorocarbonliquid during inspiration. As that Example demonstrates, there was arapid increase in tracheal pressure due to airway constriction. Airwaydilation, on the other had, has also been demonstrated with the additionof other biological agents, such as isoproterenol and epinephrine, to aperfluorocarbon ventilation liquid.

The embodiment of the invention pertaining to the pulmonary delivery ofbiological agents can also be useful for diagnosing particularconditions, diseases and/or abnormalities in the pulmonary system. Forexample, contrast agents (e.g., radioopaque agents) can be augmentedinto the liquid medium to enhance structural delineation of thepatient's pulmonary air passages. Moreover, agents which can evaluatediffusional barriers, pulmonary blood flow, and/or distribution ofventilation can also be employed.

When practicing any embodiment of the invention, it is generallynecessary to monitor and/or control certain mechanical and/orphysiological parameters. The particular parameters which would fallinto this category will depend greatly upon specific circumstancessurrounding the specific application. Examples of variables which aregenerally taken into consideration when practicing the inventioninclude, but are not limited to: the technique being employed for liquidventilation/lavage, the particular pulmonary condition being treated,diagnosed and/or controlled the particular method of treating,diagnosing and/or controlling the particular condition, and the likesand/or any combination thereof.

Parameters which are most often monitored and/or controlled generallycan be divided into three categories. The first category includes themonitoring and/or control of parameters, such as breathing frequency,inspiratory and expiratory times, volume, flow rate, and/or pressure.The second category includes the monitoring and/or control ofparameters, such as the temperature of the inspired liquid. The thirdcategory includes the monitoring and/or regulation of parameters, suchas oxygen and carbon dioxide tensions of the inspired liquids. While theaforementioned list of categories includes those parameters which aremost likely to be monitored and/or controlled, is not intended to be anexhaustive list.

As can be seen from the above disclosure, the pulmonary administrationof biological agents through at least a portion of the patient's airpassages is also a means to directly access cardiac output for theinfusion of selected agents when systemic collapse precludes deliveryvia intravascular administration.

As stated earlier, any suitable technique can be employed to combine theselected biological agent and the selected liquid carrier. While notnecessarily the preferred technique, one of the many examples of anapparatus and method for producing a uniformly dispersed phase of abiological agent in a liquid medium is now described. The termbiological agent used in conjunction with the following description, isin a liquid phase or can be converted into a liquid-phase. Examples ofsuch biological agents include, but are not limited to, exogenoussurfactants, antibiotics, steroids, antioxidants, antiprotease,bicarbonate, and other similar chemotherapeutic and/or diagnosticagents.

This representative apparatus produces a cloud or liquid-liquid mist ofuniformly sized agent-containing droplets with a liquid carrier (e.g., aperfluorocarbon liquid), wherein the droplets are a uniformly dispersedphase and the liquid carrier is a continuous phase. This method isuseful for producing agent/carrier combinations that form a dispersionor suspension (where the carrier and agent are immiscible to asubstantial degree), or a solution (in the case of solubleconstituents).

Referring to FIG. 38, an apparatus 208, that can be used to provide auniformly dispersed biological agent within a source of a liquid carrier210, includes a longitudinal conduit 212 that carries theagent-containing fluid to a delivery device (not shown) for introducingliquid 210 in the at least a portion of the patient's pulmonary airpassages. Along the length of conduit 212, upstream from the end whereliquid 210 enters the preselected pulmonary air passages, is header 214.

Header 214 is divided into an inner chamber 216 and an outer chamber218. Inner chamber 216 occupies the central portion of header 214, andouter chamber 218 surrounds inner chamber 216 and occupies the balanceor outer portion of header 214. The upstream end of inner chamber 216communicates with source 220 for the aqueous solution or otherliquid-phase biological agent(s) 220 through conduit 213. Outer chamber218 communicates with liquid carrier source 210 through conduit 211.Although conduit 211 is illustrated as being of the side of header 214,it can also be on the top or bottom of header 214 or on the side whereconduit 213 joins the header. Inner chamber 216 and outer chamber 218are separated from each other so mixing of the aqueous solution or otherliquid-phase agent(s) and the liquid carrier, within header 214, isprevented.

Downstream end of outer chamber 218 includes a plurality of orifices 224through which liquid carrier 210, within outer chamber 218, can pass inan evenly distributed manner into conduit 212. Liquid carrier 210 flowsthrough conduit 212 in the direction of arrows 226.

Downstream end of inner chamber 216 communicates with upstream end of aplurality of longitudinal tubes 228 that extend lengthwise in adownstream direction within the central portion of conduit 212. Thedownstream end of each tube 228, opposite inner chamber 216, includesnozzle 230. When the solution of biological agent(s) is forced throughnozzle 230, small droplets 234 are formed. The plurality of tubes 228are spaced apart in a side-by-side relationship so that liquid carrier210, which enters conduit 212 through orifices 224, can flow between andaround tubes 228.

In most cases, the length of tubes 228 will be such that liquid carrier210, which passes through orifices 224, can achieve a laminar flowbefore passing by nozzles 230. Laminar flow is preferred so that thedispersed droplets of the aqueous solution or other liquid-phasebiological agent(s), as described hereinbelow in more detail, will beuniformly dispersed throughout liquid carrier 210.

Upstream from nozzles 230 and downstream from inner chamber 216, tubes228 are supported by a plate 232 that passes upward, perpendicular tothe longitudinal axis of tubes 228, through the top side of conduit 212.Plate 232 supports each tube 228 near nozzle 230 so that nozzles 230 arepositioned uniformly and substantially in the center of conduit 212. Ina preferred embodiment, plate 232 is attached to a high-frequencydriver, such as an ultrasound transducer, that can vibrate the nozzles230 at a high frequency to stimulate the natural instability of thedroplets that form at the nozzles' tips and promote the formation of thesmall droplets of controlled size. The vibration can be in a verticalplane or a horizontal plane relative to plate 232. As an alternative tovibration, controlled-size droplets of the aqueous solution or otherliquid-phase biological agent(s) can also be formed by providingoscillatory pulses of pressure to the liquid in tubes 228. Pressurizingthe liquid in tubes 228 can be accomplished by pulsing the source 220pressure of the aqueous solution or other liquid-phase agent(s) atappropriate frequencies.

In operation, liquid carrier 210 is introduced into outer chamber 218through conduit 211. Liquid carrier 210 fills outer chamber 218 andpasses through orifices 224 and into conduit 212 where it passes downconduit 212 and in between and around tubes 228.

An aqueous solution or other liquid-phase biological agent(s) isintroduced into inner chamber 216 through conduit 213. The solutionfills inner chamber 216 and enters tubes 228. The solution exits tubes228 through nozzles 230 which produces small, uniformly sized droplets234 of the solution. Since liquid carrier 210 surrounds nozzles 230, thedroplets of liquid drug are dispersed into the liquid carrier as theyseparate from nozzles 230. Formation of uniformly sized droplets ofpreferred diameters may be promoted by either vibrating plate 232 or byproviding oscillatory pulses of pressure to the source of the aqueoussolution of liquid-phase agent(s) as described above.

The size of droplets 234 can be controlled by varying the size and shapeof the nozzles, the temperature of the source liquid 220, and/or themean pressure provided from the source of the aqueous solution or otherliquid-phase drug(s). In addition, the frequency, magnitude, and shapeof the oscillation signal (e.g., sine wave vs. square wave) of thevibration, or the frequency and magnitude of the pulses of pressure, canbe modified to selectively control the size of the droplets. Otherfactors such as drug vehicle temperature and chemical additives thateffect physical properties (e.g., surface tension and viscosity) of thecarrier 210 liquid (without changing the therapeutic effects or toxicityof same) can also be manipulated to control the formation of thedroplets.

It should be understood that the apparatus described above is but onerepresentative embodiment by which one can achieve this liquid-liquidmist of uniformly sized droplets in a carrier liquid. The motivation tointroduce drugs in this manner is particularly important with immiscibleliquids of substantially different densities, such as in the case withaqueous-based drugs and perfluorocarbon liquids. By introducing thedispersed drugs in the flow stream just before entering the patient, thetime for buoyancy-driven separation of the two constituents is minimizedand the biodistribution of the drug is thereby enhanced.

It should also be understood that the embodiment of the inventionpertaining to the pulmonary administration of drugs also includes theadministration of solid, insoluble drugs. In these instances, forexample, a liquid-solid phase may be formed by dispersing and/orsuspending a fine powder of the drug in the liquid carrier.

The examples which follow are intended to assist in a furtherunderstanding of the invention. Particular materials employed, species,and conditions are intended to be illustrative of the invention and arenot limitative of the reasonable scope thereof.

EXAMPLES

Based on the well-established biocompatability of perfluorocarbonliquids, the issues most central to determining the feasibility of thedisclosed convection and ultrasound hyperthermia techniques were thosehaving to do with the fluid, thermal, and acoustic characteristics ofperfluorocarbon liquids and lungs filled with perfluorocarbon liquids.Below, the general physical, thermal, and acoustic properties ofcandidate liquids are quantified in parameter ranges appropriate to lungheating, as confirmed by isolated lung and in vivo experiments. Byemploying perfluorocarbon liquids that meet the disclosed criteria, wehave demonstrated sustained and controlled convective and ultrasoundhyperthermia in large animal lungs in vivo.

A thorough investigation of the requisite properties of candidateperfluorocarbon liquids was undertaken. From these studies, the mostsuitable class of liquids was selected for use in confirming animalresearch. As described below, perfluorocarbon liquids were found toexhibit interesting acoustic properties leading to unexpected but, forthe most part, favorable behavior for the purpose of liquid-filled lungultrasound hyperthermia (LLUH). Chief among the findings are: a) pureperfluorocarbon liquids show measurable nonlinear acoustical behavior inintensity ranges suitable to LLUH (<2 W/cm² @1 MHz), i.e., attenuationincrease with power as well as frequency; and b) perfluorocarbons in thelung exhibit significant acoustical scattering of the ultrasound beam.The implications these observations have on the LLUH devices include 1)the need for lower frequencies than are used in conventional superficialultrasound hyperthermia, 2) a natural advantage exists whereby inherentacoustic beam profile “smoothing” (i.e., flattening of the nearfielddiffraction peaks) occurs due to augmented scattering, and 3) apotential benefit favoring focused ultrasound devices may exist in thatpreferential absorption in their focal regions should result from thenonlinear properties of these particular liquids. In addition, thephysical properties of perfluorocarbon liquids have yielded someunexpected advantages. Chief among these are a) the tremendous gassolubility of the liquids make them unique in their ability to quicklyand completely fill lung tissue, an advantage important for acousticcoupling, and b) the high gas solubility can likely be exploited tosuppress cavitation in the liquid. In addition, the low surface tensionsof perfluorocarbon liquids, as shown in FIG. 8, enhance the liquid'sability to readily fill the lung. Also, when a lung becomes filled withliquid, liquid resides on both sides of the vascular spaces, that is, onboth the gas side and the blood side. By regulating the amount of liquidinfused into the lung space, the blood flow can be controlled. This isbecause the more fluid that is introduced, the more compressed the lungcapillaries become. Reduced blood flow is an important mechanism toreduce heat dissipation and therefore to further localize the treatmentto the desired target tissues. Also, the liquid distribution in the lungcan be used to control the distribution of pulmonary blood flow.

A wide range of perfluorocarbon liquids were initially considered in anevaluation of physical, thermal, and acoustic properties for selectingthe most apt liquids for liquid-filled lung procedures. A summary ofthese properties is described in detail below.

Example 1

General Characteristics of Perfluorocarbon Liquids

Physical properties: The candidate perfluorocarbon liquids spanned awide range of molecular weights, as indicated in FIG. 7. For referencepurposes, the physical properties of the liquids are presented in theFigures in order of molecular weight, with water properties included forcomparison, and, unless otherwise stated, are measured at 25° C.

Fluid flow properties: The predominant force involved in lung inflationis the surface force along alveolar walls due to the action of surfacetension effects from the moist lining of the alveoli. The introductionof bulk liquid into the lung significantly reduces these forces sincethe gas/liquid interface is removed. Further reducing these forces isthe fact that perfluorocarbon liquids have some of the lowest surfacetensions recorded for liquids (FIG. 8). These combined effects meansthat the net pressure to maintain inflation in a PFC-filled lung isroughly 20-30% of that required for air inflation [61]. This fact isadvantageous for providing cuff isolation of lung lobes and segmentssince cuff sealing in the airways can be accomplished with lowerpressures than for normal clinical bronchial intubation.

Perfluorocarbon liquids are generally poor solvents, being essentiallyinsoluble in water, alcohols, and most biological materials. This is aprimary key as to why they are superior to saline as acousticcoupling/heat transfer fluids for liquid-filled lung ultrasound andconvection hyperthermia treatments. This immiscibility ensures that thephospholipid surfactant (which maintains low surface tension in alveolarwall moisture) will not readily be washed out of the treated lung. Thisin turn minimizes the respiratory difficultly which might otherwiseoccur in a lung after returning to gas ventilation [62].

To reduce liquid flow resistance into and out of the lung it isimportant to minimize the effects of viscous resistance. FIG. 9 showsthat some of the perfluorocarbon liquids considered are relatively highin absolute viscosity, compared to water. On this basis, liquids withmolecular weights (see FIG. 7 for molecular weights) higher thanF-Decalin (i.e., perfluorodecalin) become less desirable. Strictlyconsidered, flow resistance is more closely related to the “kinematicviscosity” (absolute viscosity/density) than absolute viscosity, usuallyas expressed in the “Reynolds Number” [63]. Considering the higherdensities of the liquids (FIG. 10), it is found that thoseperfluorocarbon fluids with molecular weights below F-Decalin have flowresistance characteristics equivalent to or better than water.

Gas solubility: To illustrate the tremendous capability ofperfluorocarbon liquids to absorb dissolved gases, FIG. 11 shows theoxygen solubility of six perfluorocarbon liquids in comparison withwater. From the standpoint of exploiting this property to suppresscavitation, to assist in lung filling, and, of course, to enablesimultaneous lung ventilation during liquid-filled lung hyperthermictreatments (via ultrasound and/or convection), the perfluorocarbonfluids are all roughly equivalent, with a slight preference going tomolecular weights below F-Decalin.

Example 2

Thermal Properties of Perfluorocarbon Liquids

Thermodynamic properties: In ultrasound lung heating if will beundesirable to induce boiling in the coupling liquid since, at the veryleast, this will interrupt acoustic coupling. As shown in FIG. 12, thiscriterion renders FC-72 a very poor liquid selection, and RM-82 andFC-84 less than optimum as well. In this category, RM-101 and FC-75roughly match the boiling points of tissues, so they are acceptable,though not as appealing as the higher molecular weight fluids.

The efficient removal of perfluorocarbon liquid from the lung afterliquid-filled lung hyperthermia treatments must be a leadingconsideration in designing the proposed therapies. The primary removalmechanisms for the bulk liquid will be first pumping or suctioning thefluid from the lung, permissibly followed by gravity-induced drainage(enhanced by the high densities of perfluorocarbons). The remainder ofthe fluid is then removed by evaporation. The facility with which aliquid evaporates is expressed by its vapor pressure; the higher thevalue, the more rapid the evaporation. As FIG. 13 demonstrates,perfluorocarbon liquids with molecular weights above F-Decalin areclearly unacceptable from this standpoint. It is not surprising that themost favorable liquids in this category (FC-72, RM-82, and FC-84) arethe same ones that were undesirable from a boiling point perspective,since the physical phenomena are the same.

Heat transfer properties: The ability to convectively transfer heat tothe lung will be governed by the “Prandtl number” of the fluid, whichdefines the ratio of viscous diffusivity to thermal diffusivity, i.e.,the ratio (specific heat)×(viscosity)/thermal conductivity [64]. Becausethe specific heat for perfluorocarbon liquids is virtually constant(0.25 J/g-C) and since their thermal conductivities only vary by about20% (k_(ave)=0.064 W/m-C), a Prandtl number comparison is dominated bydifferences in viscosity (see FIG. 9). Thus, from this standpoint, allfluids with molecular weights below F-Decalin are generally preferredand are approximately the same.

The ability to sustain constant temperatures in the lung is determinedby the “thermal capacitance” of the fluid, or (density)×(specific heat).Again, because there is no variation in specific heat between thefluids, the more dense fluids will be those with higher thermalcapacitances.

Example 3

Laboratory acoustic measurements: For the purpose of obtainingattenuation data over the range of physical parameters described, aspecial Perfluorocarbon Fluid Conditioning and Acoustic Measurement FlowSystem was constructed, as depicted schematically in FIG. 14. Thissystem permitted low volumes of perfluorocarbon liquid (<1 liter) to beconditioned to any desired temperature and gas saturation level whileexposing the liquid in a transparent fluid sample cell to ultrasound.The fluid sample cell featured thin membrane (1 mil Monokote) on the topand bottom surfaces, allowing virtually loss-free coupling of the soundto the cell via temperature-controlled degassed water. Sound attenuationwas measured via the force balance method, which detects acousticradiation pressure [65]. The sound traversed the sample cell and wasthen absorbed by an absorber plate suspended from a precision load cell.The acoustic path length through the perfluorocarbon liquid was 5.0 cm.An adjustable-height base plate below the absorber was adjusted toreduce oscillations in the absorber through the action of viscous fluiddampening. The radiation forces were recorded by a digital voltmeterconnected to the load cell, with the voltage signals representing forceautomatically sent to a computer where the data was converted toacoustic power in Watts and stored for later analysis. To accommodatethe need for frequencies below 1.0 MHz, both 250 and 500 KHz powertransducers were constructed.

Cavitation is a complex function of temperature, fluid properties, fluidpurity and cleanliness, ambient pressure, and gas content. For thepurposes of this study, clean perfluorocarbon liquid was used andmeasured over a temperature range from 25° to 45° C. and at gassaturations from a completely degassed state to 100% saturation usingair, O2, and blood gas (7%, O2, 7% CO2, balance N2). Cavitationthresholds were determined primarily by high-speed video camerarecording, by still photography, and by visual inspection for bubbleformation through the transparent sample cell walls. Sound speeds weremeasured by frequency-matched ultrasound transmitter/receiver transducerpairs separated by a known and fixed gap. A single-path, time-of-flightmethod of velocity measurement was employed using an oscilloscope.

Perfluorocarbon liquids have sound speeds which are among the lowestrecorded for any liquids (FIG. 15). To obtain efficient coupling of thebeam into the perfluorocarbon liquid from either water or tissue, theliquid's acoustic impedance, (density)×(sound speed), shouldapproximately match that of water and tissue. Whereas the soundvelocities are indeed very low in perfluorocarbon liquids, their higherdensities favor a good acoustic impedance match, as shown in FIG. 16.FIG. 17 shows comparative values of perfluorocarbon acoustic impedances.Although FC-5311 shows an almost perfect match, this liquid isill-suited for use in liquid-filled lung hyperthermic treatments on thebasis of the physical properties discussed above. The remaining acousticmatching values, while not ideal, can provide good coupling of soundbetween water and tissue. For example, the transmission loss of soundpassing from water into FC-75 is only slightly over 3 percent.

Example 4

Acoustic Properties of Perfluorocarbon Liquids

Acoustic measurement materials and methods: Ultrasound transmission isprimarily governed by attenuation in the perfluorocarbon liquids and, atrelatively higher intensities, cavitation (i.e., creation of smallbubbles by gases liberated out of solution). Lab measurements of soundspeed, impedance, attenuation, and cavitation were done in severalperfluorocarbon fluids over a temperature range from 25° to 45° C. andat various gas saturations representative of conditions anticipated inliquid-filled lung hyperthermic treatments in a special PerfluorocarbonFluid Conditioning and Acoustic Measurement Flow System (depictedschematically in FIG. 18).

Blood perfusion in liquid-filled lungs is much lower than under normalphysiological conditions, particularly when the lung tissue beingtreated is not simultaneously ventilated. In addition to enhancing thelocalization of the treatment, as discussed above, by virtue of reducingblood perfusion dissipation of thermal energy, the ultrasound powerrequired for lung hyperthermia is surprisingly lower than might beappropriate for other vascularized tissue, e.g., muscle. The acousticintensities employed for the evaluation of perfluorocarbon acousticproperties ranged from 0-3.5 W/cm² and are expected to fully encompassthe range appropriate for lung heating. Somewhat higher output powerswere used in the cavitation evaluations. In addition, althoughproperties were measured at frequencies of 0.25, 0.50, 0.90, 1.0, 1.1,and 2.25 MHz, only the range from 0.25 to 1.1 MHz was studied in detaildue to the high attenuation associated with 2.25 MHz sound. Thefollowing observations were made.

Acoustic impedance: Perfluorocarbon liquids have sound speeds which areamong the lowest recorded for any liquids. To obtain efficient couplingof the beam into the perfluorocarbon liquid from either water (ortissue), the liquid acoustic impedance, (density)×(sound speed), shouldapproximately match that of water and tissue. Whereas the soundvelocities are indeed very low in perfluorocarbon liquids, their highdensities favor acoustic impedance matching, as shown in FIG. 16(perfluorocarbons listed according to molecular weight). For example,the transmission loss of sound passing from water to FC-75 is onlyslightly over 3 percent.

Acoustic attenuation: The most surprising acoustic characteristic ofperfluorocarbon liquids was found to be their low threshold forexhibiting nonlinear behavior. FIG. 19 shows the attenuation behavior ofFC-75 by comparing the acoustic power transmitted through 5 cm ofdegassed water (virtually loss-free) versus that through FC-75 at 1.0MHz. It can be seen that the attenuation gradually increases with power(electrical power is normalized by the transducer face area andexpressed as Electrical “Intensity”), even over the moderate powerlevels required for lung heating. The liquid attenuation is, however,extremely sensitive to frequency. As shown in FIGS. 20 and 21, theattenuation and the degree of non-linearity fall dramatically at lowerfrequencies, showing virtually loss-free behavior at 250 and 500 KHz(within the limits of accuracy of the measurement method). Theattenuation in perfluorocarbon liquids also increases as the fluids areheated, as depicted in FIG. 22. This is an interesting nonlinear aspectas well, for attenuation in water and most fluids decrease withtemperature, due to the reduction of viscosity. Although perfluorocarbonattenuation increases with temperature, the use of low frequencies cancompensate, resulting in very low losses, as the 250 KHz, T=45° C. dataof FIG. 23 show. FIG. 24 compares the attenuation in threeperfluorocarbon liquids representing a significant range of molecularweights.

Cavitation: While the bio-effects of acoustic cavitation are apparentlytolerated in some therapeutic applications [55], in principle it will bebetter to avoid it in the liquid-filled lung. The data obtained in theseexperiments have shown that cavitation is likely to occur at ultrasoundintensity levels only if the perfluorocarbon liquid is at or very nearits saturation point in terms of dissolved gases (e.g., O2 or bloodgases). Thus, it will not be advisable to support respiration in thelung with 100% O2 saturated liquids while using ultrasound heating.However, this does not preclude the use of incompletely gassed liquids(e.g., 75% saturation) for use in simultaneous ventilation withultrasound hyperthermia.

Also, it should be emphasized that simultaneous 100% O2 liquidventilation support while convectively heating the lung is feasible.FIG. 25 shows the power dissipation which occurs from cavitation in 100%saturated FC-75 over the hyperthermic temperature range. This data alsoindicates that no cavitation occurs in degassed liquids. Some variationof the threshold for cavitation in gas-saturated liquids was found as afunction of frequency as well as of temperature.

It is important to stress that even slight degassing seems effective insuppressing cavitation at these intensities. This is probably due to thetremendous perfluorocarbon affinity for gases. Perfluorocarbons appearless prone to cavitation at equivalent saturations and intensities thanwater. The perfluorocarbon capacity to dissolve gases is so high, infact, it is difficult to cavitate liquids at the recommended ultrasoundpowers even a few percent below saturation, as seen in FIG. 18 (wheregas saturation is changed in small increments by changing liquidtemperature). Because of both decreased lung perfusion duringliquid-lung procedures and the large “gas sink” characteristics ofperfluorocarbon liquids, it is plausible that the pulmonary circulationwould take several minutes to saturate degassed perfluorocarbon liquidsintroduced into the lung, particularly considering that the partialpressure of H₂O vapor may preclude sufficient dissolved gas saturationconditions from occurring at all. Completely degassed liquids were usedin the animal experiments (described below). The liquids were cycledinto and out of the lung (several minutes apart) to maintain low liquidgas levels.

Summary

On the basis of the foregoing experimental observations, thefluorocarbon liquids FC-75 (a mixture of perfluorobutyltetrahydrofuranand perfluoropropyltetrahydropyran; 3M Company, Minneapolis, Minn.) andRM-101 (a mixture of Furan,2,2,3,3,4,4,5heptafluorotetrahydro-5-(nonafluorobutyl) and2H-Pyran,2,2,3,3,4,4,5,5,6-nonafluorotetrahydro-6-(nonafluorodecafluoro);MDI Corp., Bridgeport, Conn.) were found equally suitable as ultrasoundtransmission and heat transfer fluids in the lung. Reinforcing theselection of these fluids (which, in purified form, should besubstantially free of hydrogen) is the fact that both have been used inanimal liquid ventilation research and have excellent records ofbiocompatibility [3]. FC-75 and RM-101 are thus consideredrepresentative of the class of perfluorocarbon liquids, most suitablefor liquid-filled lung convection and ultrasound procedures, having themost preferred physical, thermal, and acoustical parameters. Since FC-75is representative of this class, the presentation of its properties willbe emphasized from this point on.

EXAMPLE 5 Acoustic Properties of Perfluorocarbon-Filled Lungs

Animal Model/Study Design

Due to their size and structure, adult sheep lungs are good pulmonarymodels. In the following animal experiments, five adult sheet were usedin acute in vivo and in vitro studies. A narrow band, 1.0-MHz, 6-cmdiameter piezo-ceramic disk transducer with an integral temperaturecontrolled coolant/coupling liquid was utilized for these studies. Boththermal techniques (measuring specific absorption rates (SAR) of power)and acoustic methods (measuring acoustic pressures and intensities) wereemployed. The animal preparation and experimental methods employed forthe in vivo studies are described in detail below.

Animal Preparation

Following the methods normally used in ongoing liquid ventilationresearch, the animals were all initially given pentobarbital sodium (20mg/kg) to induce deep sedation. After a local infiltration of 1%lidocaine in the neck, the right carotid artery and right jugular veinwere cannulated. A tracheotomy was performed for the placement of eitheran indotracheal tube or a liquid infusion catheter (the catheter shownin FIG. 1 could be used for this purpose). To maintain biologicalstability, the sheep's untreated lungs are ventilated on a mechanicalventilator at a volume of 500 ml, at a frequency of approximately 15-20breaths per minute, under skeletal muscle paralysis (pancuroniumbromide; initial bolus of 0.1 mg/kg, followed by 0.1 mg/kg/hr). Inaddition, steady state maintenance of the animals included anintravenous crystalloid infusion (10% dextrose with 10 mEq sodiumbicarbonate and 1 mg sodium pentobarbital/100 ml fluid) administered ata rate of 3 ml/kg/hr. Physiological monitoring was done via arterialblood gas tensions, pH, heart rate, and blood pressure measurements.Additional surgical procedures during in vivo experiments includeddouble or triple rib resections, to expose an acoustic window for theultrasound applicator. Also, small needle thermometry probes wereinserted in deep muscle and in the isolated region of the lungs(described below). All animals were euthanized with magnesium chloride.

Liquid-Filled Lung Procedures

To quantify acoustic properties in perfluorocarbon-filled lungs invitro, a series of experiments were performed on isolated adult sheeplungs. There is a striking visual difference between a normal air-filledlung and one which is filled with fluorocarbon liquid. The glisteningdark red color characteristic of the successfully filled “liquid lung”was one measure of a lung reaching complete filling. In addition,measurements of acoustic propagation were also used to confirm thedegree of filling. It was found, both in the in vitro and in vivo cases,that the lung filling process could be accomplished in about one-quarterof the time previously required for perfluorocarbons if the liquid werecompletely degassed prior to the initial infusion (only 1-3 minutes).The enhanced filling process was due to the perfluorocarbons' ability todissolve great quantities of gas, rather than simply depend ondisplacing the trapped alveolar air. It was found that saline fillingrequired much more time than for the fluorocarbons using partiallydegassed liquids.

In vitro Ultrasound Experimental Materials and Methods

In vitro ultrasound characterizations were performed with an applicatorconsisting of a narrow band 1.0-MHz, 6-cm piezo-ceramic disk transducerwith temperature controlled coolant/coupling liquid continuouslysurrounding it. The system was capable of delivering 150 Watts ofacoustic power, though these power levels were in excess of thatrequired for fast warmup and certainly much more than was required forstable steady state lung hyperthermia.

The isolated lungs were instrumented either with thermocouple probes (29gauge) or with ultrasound hydrophones for thermal or acousticdeterminations of attenuation, respectively. Acoustic gel was used toinsure good coupling into the tissue. The thermal technique used wasthat of determining the Specific Absorption Rate (SAR) from the initialrate of temperature rise [66 ]at different depths in the lung. Ratios ofSAR at the various depths yielded attenuation. The hydrophonemeasurements recorded dynamic pressure variations directly which weredisplayed on an oscilloscope. Squaring of the pressure data resulted indata proportional to intensity, which could then be translated toattenuation values for known acoustic path lengths.

In Vivo Liquid-Lung Ultrasound Hyperthermia Materials and Methods

To provide efficient filling of the lung lobe, completely degassed FC-75was introduced through a conventional clinical bifurcated bronchialcatheter that permitted infusion of the selected lung lobe whilesustaining gas ventilation in the remainder of the lung. The catheterwas placed without benefit of a bronchoscope, so the correct placementhad to be determined by verification of lung inflation motions in thedesired lung segments. The perfluorocarbon liquid was introduced at roomtemperature and only infrequently circulated in and out. In most casesthe cranial segment of the right apical lobe was chosen for selectiveheating, both in the ultrasound and the convective hyperthermiaexperiments.

These segments had inflated volumes of approximately 250-300 ml. An“acoustic window” to the lung segment was obtained by resection ofportions of three ribs essentially analogous to an intraoperativehyperthermia treatment. The treated lung segment was partiallyexteriorized through the “window” to enable invasive thermometry of thetreated lung at different depths. The sound was propagated directlythrough coupling water and membrane into the lung. In most cases, thelung surface was cooled with 37° C. coupling water.

In addition to heating data, in vivo acoustic measurements were alsoperformed via the hydrophone method previously described. Continuousrecording of relevant physiological parameters were performed throughoutthe experiments. These measurements included systolic and diastolicblood pressure (reduced to Mean Arterial Pressure), core temperature,heart rate, and respiration rate. Gas ventilation was maintained by amechanical respirator. Cardiopulmonary stability was confirmedthroughout the treatments by taking periodic blood samples for arterialpH, pO₂, and pCO₂.

In Vitro Ultrasound Results

FIG. 26 presents typical in vitro attenuation values for isolated lungof an adult sheep. The attenuation shows a significant increase withincreasing frequency. Note also that the attenuation levels are higherin the liquid-filled lung than for the pure liquid. It is postulatedthat this augmented attenuation is mostly attributable to scatteringfrom the refraction effects of the sound speed mismatch between theparenchymal tissue and the liquid (increased scattering is supported bythe ultrasound imaging results as well). Because scattering increasesthe effective acoustic path length, a wave traverses and spreads thebeam slightly, the near loss-free propagation for lower frequencies(e.g., 250 and 500 KHz; FIGS. 20, 21, and 23) in perfluorocarbon liquidsis no doubt preferred to frequencies above 1 MHz for deeperhyperthermia. Lower frequency ultrasound should also exhibitsignificantly reduced scattering since the wavelength increasessubstantially (e.g., to 3-6 mm) in relation to the main scatteringstructures (i.e., bronchioles, diameters <1 mm [56]).

FIG. 27 demonstrates that the liquid-filled lung acoustic properties aredominated by the presence of the liquid (this likely also holds true forthe thermal properties). This data shows that the effective sound speedsmeasured (both in vivo and in vitro) are close to those of the pureliquid (dashed line). Note that connective tissue sound speeds areusually higher than those of blood and muscle.

Example 6 In Vivo Acoustic Lung Hyperthermia

Employing the methods and protocols described in Example 5, sustainedhyperthermia (42-45° C. to about 4 cm depth for 30 minutes) wassuccessfully accomplished in the two animals used for the tests. Thetemperature vs. depth histories which resulted are represented by FIG.28, which depicts the experiment employing the greatest number oftemperature probes. In this case probes were located in the interstitialtissue along the beam central axis at depths of 0.5, 1.0, and 2.0 cm,and also at 3.0 cm but slightly off axis. In addition, an on-axis probewas placed on the distal surface of the lung segment (approximately 6 cmfrom the treatment surface) between the lung surface and a rubber mat(which also acted as an acoustic absorber). As shown, lung temperaturesexceeded 43° C. to approximately 3 cm depth, with acoustic penetrationthrough the lung segment indicated by the high temperatures on thedistal surface (effectively 6 cm deep). The close tracking of the 2 and3 cm depth temperatures (again, not in line with each other) may havebeen due to refractive effects or differences in local perfusion. Thelower temperature at the 0.5 cm site is due to the conductive cooling ofthe coupling water (at 37° C.). The “thoracic cavity” core temperatureprobe was located near the treated segment in the cavity. The steadystate power requirements in this case ranged between 12 to 15 Watts,again indicative of low pulmonary perfusions due to the liquid presence.

Perfusion Response of the Liquid-Filled Lung

The ultrasound power levels required for steady state hyperthermia wereunexpectedly low due to low blood flow levels in the heated lung. Ananalysis of the physiological mechanisms involved, however, indicatesthat the perfusion is suppressed due to the combined effects of: 1)increased pulmonary vascular resistance due to the presence of theliquid compressing alveolar capillaries, 2) the shunting of thepulmonary circulation to other areas of the lung from locally low pO₂(here from degassed liquids), and 3) to shunting from a low pH buildupin the lobe [29, 30, 31].

Example 7 In Vivo Convective Lung Hyperthermia

Convection Hyperthermia Materials and Methods

Using the large animal liquid ventilation (LALV) system of TempleUniversity (FIG. 29), heated, temperature-controlled FC-75 could becirculated in and out of lung lobes and segments isolated via thebifurcated bronchial catheter method as described above. The animalpreparation was essentially the same as for the ultrasound experiments.In this way convective lung hyperthermia was successfully administeredto the cranial segment of the right apical lung lobe. To instrument thelung so that temperature probes could be easily placed at known depths,the lung segment was partially exteriorized through a “window” createdin the same manner as was done for the ultrasound experiments.

FIG. 30 shows the temperature history data for the convective lunghyperthermia experiment. The setup period was used for establishingproper placement and sealing of the liquid delivery catheter, for propertemperature probe placement, and to assess the response of the lung toLLCH parameter changes. It was found that the very thin wall (≈2 mil)vinyl air cuffs on the available bifurcated catheters had very littlestructural integrity at the elevated liquid temperatures required of thehyperthermic treatment. As such, the catheters provided adequate, butnot high quality, sealing. Although this had very little physiologicalimpact (since the gas ventilation of the remaining lung was quiteadequate), it did result in diminished heat transfer rates. Thedevelopment of a suitable liquid delivery catheter was thereforemandated.

During the experiment, the heat transfer to the lung segment was variedby changing both the inspiratory liquid temperature (T_(ins)) and thetidal volume (V_(t)) under constant cycling (5 “breaths” per minute)conditions. Beginning with a low T_(ins), low V_(t) condition (43° C.,40 ml), it was found that temperatures in the therapeutic range slowlyfell below hyperthermic values. Lung perfusion effectively cooled thelung under these conditions. However, increases in T_(ins) and V_(t)overcame this decline, bringing temperatures back up above 45° C. (t ≈60minutes). Once the lung has reached the desired therapeutic temperature,the T_(ins) and V_(t) settings were adjusted downward to maintain goodsteady state hyperthermia (t>60 min).

Noteworthy Trends

First, the temperature probes in the center of the lung segmentinterstitium (spaced 2-3 cm apart) consistently were within 0.5° C. ofeach other at the higher tidal flows (t>60 min), and were usually within1° C. of each other at the lower flows (t<40 min). Therefore, spatiallyuniform heating can readily be achieved and controlled via the tidalflow. Secondly, the rates of lung temperature increase shown during theexperiment (≈0.25 C/min) are much more sluggish than rates which shouldoccur at similar T_(ins) values in a properly designed clinical device.This is due to the aforementioned compromised heat transfer from theleaky catheter cuff. Indeed, much higher rates were found during thesetup period prior to cuff leakage (≈1 C/min for t<25 min). Lastly, itshould be noted that steady state lung temperatures closely trackedT_(ins), which was measured outside the animal in the liquid circuit. Byplacing a temperature sensor at the distal end of the catheter, at theentrance to the heated lung lobe or segment, the lung temperaturesshould be known with a high degree of certainty. This is significant inthat there should be no need for invasive lung thermometry during thesubject treatment.

Example 8 Ultrasound Imaging for Liquid-Filled Lung Procedures

The presence of liquid in the lung theoretically makes possible the useof ultrasound imaging, both for viewing lung structures and for use inconjunction with the ultrasound and convection treatments. Both in vitroand in vivo ultrasound imaging experiments were performed onperfluorocarbon-filled lungs as part of the animal studies describedabove. The diagnostic imaging system was a commercial clinical system(Diasonics) capable of sector-scanned images at frequencies from 3 to 7MHz. B-scan images were obtained on exteriorized perfluorocarbon-filledlung lobes and on lung lobes viewed through the rib cage andintrathoracically.

Consistent with the ultrasound results discussed previously, it wasfound that the increased attenuation and scattering of the very highdiagnostic frequencies (3-7 MHz) rendered the diagnostic value ofimaging deep lung structures through liquid-filled lung parenchyma poor.The imaging of structures through liquid-filled lung parenchyma may bethe one area where saline-filling of lungs provides a distinct advantage(due to matched sound speeds).

The foremost advantages of diagnostic ultrasound imaging in the presentapplication are for monitoring the lung-filling process and forconfirming the integrity of the acoustic path. This conclusion is basedon the distinct ultrasound images which were obtained when lung lobesreached gas-free or near-gas-free states.

Example 9 Liquid-Filled Lung Hyperthermia and Chemotherapy

The prospects for using perfluorocarbon liquids as drug deliveryvehicles may be quite favorable since commercial examples offluoropharmaceuticals are many and diverse [60]. In addition,simultaneous locally delivered anesthesia in the treated tissue shouldalso be possible via liquid delivery (though systemic anesthetic effectsmay also result). Although anesthetic use is often contraindicted inhyperthermia for safety reasons, because the maximum temperature in thelung may be set by the clinician with confidence in the subject(especially convection) treatments, simultaneous anesthesia may befeasible in this procedure. Conicidentally, fluorine-containinginhalation anesthetics account for the largest volume offluoro-compounds sold for purposes that are nonindustrial [60].

Example 10 Ultrasound Intracavitary Applicator (ICA) Experiments

FIG. 4 shows a schematic of a representative applicator head. Athin-walled piezoelectric ceramic cylinder (≈1.0 MHz resonance) waslongitudinally and circumferentially sectioned into four separate powertransducers with 120° and 240° included angles, respectively. Themultiple-transducer approach provided flexible heating patterns. Inthese studies transducers 120 and 122 were driven in parallel (forming asynchronous pair), as were 124 and 126. Depending upon whether each pairof both were driven, either 120°, 240°, or a full 360° of heating couldbe achieved along the length of the cylinder. The transducers weremounted in an applicator with self-contained cooling and an integralwater bolus for sound coupling, as depicted in FIG. 6. The diameter ofthis first engineering prototype ICA transducer was 16 mm. Smallercylinders more suitable for bronchial applications, however, can bereadily made.

The applicator was mounted on a long (1 meter), flexible tubular shaftwhich housed the inlet and exit flow channels to the coupling bolus, aswell as the RF power cables to the transducer. The water coolant flowdissipated heat to a maximum power of 100 Watts. The flow system wasalso characterized for pressure drop vs. flow rate to assure thatacceptable pressure drops could be maintained in the long, narrowcoolant channels.

The ultrasound beam quality was mapped in an acoustic test tank, whilethe thermal performance of the device was evaluated in a speciallyconstructed body cavity phantom. FIG. 31 shows the acoustic intensitymapped (via hydrophone) in water along the axial direction (z) of thetransducer, 2 cm from the surface and in the middle of the 240° arc ofenergized transducers 124 and 126. FIG. 32 presents SAR patternsmeasured in tissue-equivalent cavity phantoms by needle thermocoupleprobes at five axial positions and several azimuthal angles (measuredfrom the center of the 240° arc of transducers 124 and 126. FIG. 33shows the depth (radially outward) heating patterns in the phantom fromthe surface to 2 cm into the phantom tissue. The 100-Watt maximum poweremployed is more than will be needed for most applications.

Example 11 Liquid-Filled Lung Convection Hyperthermia (LLCH) System

FIG. 34 schematically shows a representative LLCH system. The system isconstructed under requirements applicable to clinical use. It isdesigned to maintain complete sterility of the liquids and catheters,and is modular and portable for convenient use in either a surgicaltheater or hyperthermia/oncology suite. The LLCH system provides heated,temperature-controlled perfluorocarbon liquid to the patient in eitherdegassed or oxygenated form (partially degassed liquid states are alsopossible). To impose controlled lung temperatures and heat transferrates, the tidal volume and “ventilation” frequency (cycling rate of thefluid into and out of the lung), and the input liquid temperature arecontrolled by the operator. To insure sterility, the unit employsroller-type peristaltic pumps which completely contain the liquid insterile tubing. Similarly, valves, fluid fittings, and reservoirs areeasily replaced and sterilizable, or disposable. The inspiratory andexpiratory flows, system liquid temperatures and components status aremonitored and controlled by a central computer. The computer serves asthe operator console during treatment, recording and displaying LLCHsystem parameters and invasive temperature probe data, and is also awork station for data playback and post-treatment analyses.

Example 12 Pulmonary Administration of Drugs Cardiovascular and AirwaySmooth Muscle Effect

This Example demonstrates a technique for directly deliveringbiologically active agents (i.e., acetylcholine, epinephrine,priscoline, sodium bicarbonate and sodium nitroprusside) into apatient's cardiopulmonary system, via the patient's pulmonary airpassages.

Using previously developed perfluorochemical (PFC) ventilationtechniques, similar to those disclosed in Shaffer, A Brief Review:Liquid Ventilation, and Wolfson, et al., A Experimental Approach for theStudy of Cardiopulmonary Physiology During Early Development, (see,notes 3 and 35, respectively, of literature citations, infra), pulmonarygas exchange and acid-base balance were maintained in anesthetized andtracheotomized young cats.

When testing the dose-dependency effect of the pulmonary administrationof acetylcholine [ACh], the effect after the administration of the drug(expressed as a percentage of the baseline), as a function of theconcentration of the drug, was monitored.

Here, the ACh was dispersed in the PFC liquid medium. The initial amountof ACh dispersed in the PFC liquid was 0.01 mg per each kilogram of thelaboratory animal's body weight.

The PFC/ACh liquid medium was then introduced directly into the animal'spulmonary air passages, via the endotracheal tube, during theinspiratory phase of PFC liquid ventilation.

Each of the animals tested had at least one of the following parametersrecorded before, during and after the pulmonary administration of thedrug: (a) heart rate (bpm), (b) mean arterial pressure (mm Hg), and (c)tracheal pressure (cm water). The averages for each of these recordedparameters were then calculated, depending upon the number of catstested. These calculated values are plotted on the graph in FIG. 35.

In addition to the above, the following parameters were also monitoredand/or controlled: tidal volume, inspiratory and expiratory liquid flowrate, arterial chemistry, pulmonary compliance and resistance, and/orbreathing frequency.

The dosage of ACh was then incrementally increased from 0.01 mg/kg up to1.0 mg/kg. For each incremental increase, the animals tested had atleast one of the aforementioned parameters recorded before and after thepulmonary administration of the drug.

Also for each incremental increase, the averages for each recordedparameter were calculated and plotted on the graph in FIG. 35.

Referring to FIG. 35, the data plotted therein demonstrates that, as afunction of increasing the concentration of ACh in the inspired PFCliquid, typical dose-dependent cholinergic responses to ACh showedprogressive decreases in mean arterial pressure (i.e., reflectingvasodilation) and heart rate, and a progressive increase in the peaktracheal pressure (i.e., reflecting broncho-constriction).

Another way in which the effect of the pulmonary administration of AChwas tested was by monitoring carotid pressure, as a function of time,before, during and after the pulmonary administration of the drug. Here,0.6 mg/kg of ACh was dispersed in the PFC liquid medium. The PFC/AChliquid medium was then introduced directly into the animal's pulmonaryair passages, via the endotracheal tube, during the inspiratory phase ofPFC liquid ventilation.

A tracing of the animal's carotid pressure, before, during and after thepulmonary administration of ACh, demonstrates, among other things, that(a) the carotid pressure decreased by about 40 mm Hg after the drug wasadministered; (b) the decrease in carotid pressure began almostinstantaneously after the drug was administered; and (c) the total timenecessary to decrease the carotid pressure by about 40 mm Hg was about10 seconds.

Yet another way in which the effect of the pulmonary administration ofACh was tested was by monitoring tracheal pressure, as a function oftime, before, during and after the pulmonary administration of the drug.

Here, 0.6 mg/kg of ACh was dispersed in the PFC liquid medium. ThePFC/ACh liquid medium was then introduced directly into the animal'spulmonary air passages, via the endotracheal tube, during theinspiratory phase of PFC liquid ventilation.

An observation of the animal's tracheal pressure, before, during andafter the pulmonary administration of tracheal pressure (cm water)increased by about 6 mm Hg after the drug was administered; (b) theincrease in tracheal pressure began almost instantaneously after thedrug was administered; and (c) the total time necessary to increase thetracheal pressure (cm water) by about 5 mm Hg was about 20 seconds.

When testing the dose-dependency effect of the pulmonary administrationof epinephrine [Epi], the effect after the administration of the drug(expressed as a percentage of the baseline), as a function of theconcentration of the drug, was monitored.

Here, the Epi was dispersed in the PFC liquid medium. The initial amountof Epi dispersed in the PFC liquid was 0.01 mg per each kilogram of thelaboratory animal's body weight.

The PFC/Epi liquid medium was then introduced directly into the animal'spulmonary air passages, via the endotracheal tube, during theinspiratory phase of PFC liquid ventilation.

Each of the animals tested had at least one of the following parametersrecorded before and after the pulmonary administration of the drug: (a)heart rate (bpm), (b) mean arterial pressure (mm Hg), and (c) trachealpressure (cm water). The averages for each of these recorded parameterswere then calculated, depending upon the number of cats tested. Thesecalculated values are plotted on the graph in FIG. 36.

The dosage of Epi was then incrementally increased from 0.01 mg/kg up to1.0 mg/kg. For each incremental increase, the animals tested had atleast one of the aforementioned parameters recorded before and after thepulmonary administration of the drug.

Also for each incremental increase, the averages for each recordedparameter were calculated and plotted on the graph in FIG. 36.

Referring to FIG. 36, the data plotted therein demonstrates that, as afunction of increasing the concentration of Epi in the inspired PFCliquid, typical dose-dependent sympathomimetic responses to Epi showedincreases in mean arterial pressure (i.e., reflecting vasoconstriction)and heart rate, and a decrease in peak tracheal pressure (i.e.,reflecting bronchodilation).

Another way in which the effect of the pulmonary administration of Epiwas tested was by monitoring the change in mean arterial pressure andheart rate resulting from drug delivery.

Here, 0.50 mg/kg of Epi was dispersed in the PFC liquid medium. ThePFC/Epi liquid medium was then introduced directly into the animal'spulmonary air passages, via the endotracheal tube, during theinspiratory phase of PFC liquid ventilation.

An observation of the animal's tracheal pressure, before, during andafter the pulmonary administration of Epi, demonstrates, among otherthings, a 31% decrease after the drug was administered. Moreover, anobservation of the animal's heart rate, before, during and after thepulmonary administration of Epi, demonstrates, among other things, a 33%increase after the drug was administered.

When testing the dose-dependency effect of the pulmonary administrationof priscoline [P], the effect after the administration of the drug(expressed as a percentage of the baseline), as a function of theconcentration of the drug, was monitored.

Here, the P was dispersed in the PFC liquid medium. The initial amountof P dispersed in the PFC liquid was 4 mg.

The PFC/P liquid medium was then introduced directly into the animal'spulmonary air passages, via the endotracheal tube, during theinspiratory phase of PFC liquid ventilation.

Each of the animals tested weighed approximately 3 kg. Each of thesetest animals had at least one of the following parameters recordedbefore and after the pulmonary administration of the drug: (a) heartrate (bpm), (b) mean arterial pressure (mm Hg), and (c) rightventricular pressure.

The averages for each of the aforementioned recorded parameters werethen calculated, depending upon the number of cats tested. Thesecalculated values are plotted on the graph in FIG. 37.

The dosage of P was then incrementally increased from 4 mg up to 12 mg.For each incremental increase, the animals tested had at least one ofthe aforementioned parameters recorded before, during and after thepulmonary administration of the drug.

Also for each incremental increase, the averages for each recordedparameter were calculated and plotted on the graph in FIG. 37.

Referring to FIG. 37, the data plotted therein demonstrates that, asfunction of increasing the concentration of P in the inspired PFCliquid, typical dose-dependent responses to P showed decreases in meanarterial pressure (i.e., reflecting vasodilation) and right ventricularpressure (i.e., reflecting systemic and pulmonary vasodilation). Theheart rate remained fairly constant.

Another way in which the effect of the pulmonary administration of P wastested was by monitoring carotid pressure, as a function of time,before, during and after the pulmonary administration of the drug.

Here, 12 mg of P was dispersed in the PFC liquid medium. The PFC/Pliquid medium was then introduced directly into the animal's pulmonaryair passages, via the endotracheal tube, during the inspiratory phase ofPFC liquid ventilation.

A tracing of the animal's carotid pressure, before, during and after thepulmonary administration of P, demonstrates, among other things, that(a) the carotid pressure decreased by about 30 mm Hg after the drug wasadministered; (b) the decrease in carotid pressure began almostinstantaneously after the drug was administered; and (c) the total timenecessary to decrease the carotid pressure by about 30 mm Hg was about10 seconds.

When testing the absorption effect of the pulmonary administration ofsodium bicarbonate [SBi], the concentration of SBi in the animal'sblood, as a function of time, was monitored.

Here, 10 mEq of SBi was dispersed in the PFC liquid medium. The PFC/SBiliquid medium was then introduced directly into the animal's pulmonaryair passages, via the endotracheal tube, during the inspiratory phase ofPFC liquid ventilation.

An observation of the concentration of SBi present in the animal's blood(monitored as a function of mEq/L) 30 and 120 seconds after thepulmonary administration of SBi, demonstrates, among other things, arespective 4.7% and 20.9% absorption level.

When testing the physiological effect of the pulmonary administration ofsodium nitroprusside [SNi], the physiological change in the animal'sarterial pressure and heart rate, after the administration of the drug,was monitored.

Here, 6 mg/kg of SNi was dispersed in the PFC liquid medium. The PFC/SNiliquid medium was then introduced directly into the animal's pulmonaryair passages, via the endotracheal tube, during the inspiratory phase ofPFC liquid ventilation.

An observation of the animal's heart rate, before, during and after thepulmonary administration of SNi, demonstrates, among other things, thatit did not significantly change, increase after the drug wasadministered. Moreover, an observation of the animal's arterialpressure; before, during and after the pulmonary administration of SNi,demonstrates, among other things, a 24% decrease after the drug wasadministered.

It was observed from the above that the pulmonary administration ofdrugs by liquid ventilation is an effective approach for directlydelivering therapeutic agents to the pulmonary and/or systemic systems.

Conclusions

The foregoing research was highlighted by the first in vivodemonstrations of both acoustic and convective hyperthermia of the lung,here in a suitably large animal model. Controlled and sustainedtherapeutic temperatures were maintained with relatively fewcomplications. These experiments, complemented by laboratory bench andin vitro acoustic measurements with perfluorocarbon liquids, identifiedthe important clinical requirements for liquid-filled lung ultrasoundand convection hyperthermia. Among these are a) lower ultrasoundfrequencies than traditionally used for soft tissue heating arerequired, b) traditional bifurcated bronchial catheters are inadequate,mainly due to their thin-walled air cuffs and lack of temperature andpressure instrumentation, and c) the use of degassed perfluorocarbonliquids greatly facilitates the filling of lungs. Of tremendouspractical significance are the observations that d) diagnosticultrasound imaging can be very helpful in assessing the lung filling andthe acoustic path available, and e) invasive thermometry will likely notbe required for the convection hyperthermia treatments. Additionally,the fundamental fluid and thermal design ranges appropriate to theultrasound treatment, including the range of inflation pressures,temperatures and tidal volumes, were determined.

Perfluorocarbon liquids have several unique properties. Measurablenonlinear acoustical behavior and scattering in the range of powerssuitable to hyperthermia were found in laboratory and animal tests.While dictating the use of lower ultrasound frequencies, thesecharacteristics can be advantageous for spatial smoothing of near fieldbeam patterns and may be able to be exploited for their potential toproduce localized enhanced absorption with focused ultrasound beams. Inaddition, the high gas solubility of perfluorocarbons should serve tosuppress acoustic cavitation in the liquid by retarding rapid gassaturation.

The salient design requirements for clinical devices for 1) fluidprocessing and delivery systems suitable for liquid-filled lunghyperthermia procedures, 2) intracavitary ultrasound applicators forbroncho-tracheal tumors, and 3) low-frequency external ultrasoundapplicators were also determined.

In addition to the above, the foregoing research also demonstrates theoperability and significant utility of pulmonary administeredtherapeutic agents through a liquid lavage/ventilation process.

Example 13

Biomechanical Uses of Pulmonary Liquids

The invention encompasses using liquids in the lung for theirbiomechanical effects, principally those resulting from their ability touniformly occupy lung tissue in cases where gas cannot (e.g., whereairways are collapsed or atalectic) and therefore exert pressure forceswhich are safer and more evenly distributed than gas. Such pressureeffects exerted by an incompressible fluid (again, which can be usedsimultaneously with ventilation, drug delivery or lavage) can be used toreposition, reshape (temporarily, or permanently if repeatedly applied),or control the motion of lung and surrounding tissues and organs.Representative uses include:

1) Repositioning the lungs and abdominal organs in neonataldiaphragmatic hernia, a condition in which babies are sometimes bornwith the contents of their abdominal cavity displaced well up into thechest, precluding efficient breathing and having other complications dueto the organs being out of place. Liquid inflation of the lungs withsimultaneous ventilation provides a method of easing the lungs andsurrounding displaced tissues back into more normal locations, eitherwith or without simultaneous surgery to help correct the problem.

2) Suppressing the motion of lungs for short times (either unilaterally,for a single lung, lobe or segment, or bilaterally for both lungs) forvarious reasons. For example, to decrease motion artifacts in variousdiagnostic imaging modalities, in order to still tissues for theplacement of instruments, in order to hold the lung temporarily stillduring short acting therapies, e.g., radiotherapy of lung tumors, etc.

3) Inflation of lungs for repairing pneumothorax in which the air leakinto the pleural space is through the outer pleural membrances (i.e.,not induced by leaks from the lung itself). This method may be superiorto using gas inflation of the lung (with or without applying a vacuum onthe pleural space) when the lung condition is not conducive to uniformexpansion or inflation (e.g., from disease or injury). A combination ofliquid inflation, followed by maintenance of constant pressure to holdthe shape of the lung, with or without a vacuum applied to the pleuralspace, could be used.

4) Use of liquid pressure to “mechanically” (not pharmacologically)alter pulmonary blood perfusion (i.e., via hydrostatic pressure andpulmonary vascular resistance effects), for instance to alter thepulmonary delivery of drugs. For example, changing the gravitationallyinduced top-to-bottom perfusion gradient in the lung may promote moreeven (e.g., for liquids with densities close to blood) or simply adifferent and more desired distribution of its absorption over the lungvolume. Notably, perfluorocarbon liquids are much denser than saline(the liquid most used in physiology).

Example 14

Mechanical Effects of Ultrasound

The invention also encompasses the use of ultrasound to producelocalized mechanical (nonthermal) effects in liquid-filled pulmonaryspaces. Ultrasound beams can be focused or scanned on portions ofpulmonary tissue (intercostally, intracavitarily, or intraoperatively)to take advantage of nonthermal effects. By employing appropriate powersand frequencies (typically lower than those used for hyperthermia)ultrasound can be used to agitate and mechanically stir (through aphenomenon termed “acoustic streaming”) local regions of the liquid inthe pulmonary air spaces, liquid which is in intimate contact with lungtissue, and which may or may not be carrying drugs. These mechanicaleffects can, by inducing localized convective motion in the fluid (on ascale varying from tracheal to alveolar characteristic dimensions), a)enhance drug transport in and to the lungs, b) improve the flushing ofsubstances out of the lung when using lavage, c) breakup “pluggedregions” of the airways by inducing high frequency oscillations in theliquid and in movable substances (e.g., mucus, proteinaceous fluids,inhaled particulates, etc.).

Example 15

Noncancer Hyperthermia

The invention also encompasses ultrasound hyperthermia (using all theultrasound methods and devices disclosed above for cancer) for nonlungcancer applications, for example, to a) produce localized drug actioncaused by higher local temperatures at desired locations, or b) to makefluid substances which are blocking airways less viscous through heatingthem, and thus enhance their removal, say through lavage, with orwithout mechanical effects of ultrasound being exploited.

While representative and preferred embodiments of the invention havebeen described and illustrated, it is to be understood that, within thescope of the appended claims, various changes can be made therein.Hence, the invention can be practiced in ways other than thosespecifically described herein.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

What is claimed is:
 1. A method for the delivery of a therapeutic ordiagnostic biological agent to pulmonary air passages of a patient inneed thereof comprising the steps of: combining said therapeutic ordiagnostic biological agent in the form of a solid or immiscible liquidwith a perfluorochemical liquid carrier to provide a pharmaceuticalpreparation; and administering said pharmaceutical preparation to thepulmonary air passages of said patient.
 2. The method of claim 1 whereinthe biological agent is selected from the group consisting ofantibody-linked radionuclides, vasoconstrictors, vasodilators,bronchoconstrictors, bronchodilators, anti-cancer agents, surfactants,steroids, antibiotic agents, chemotactic agents, chemotherapeuticagents, contrast agents, antioxidants and antiproteases, or acombination thereof.
 3. The method of claim 1 wherein saidperfluorochemical liquid carrier comprises a perfluorocarbon having aboiling point greater than about 55° C.
 4. The method of claim 1 whereinsaid perfluorochemical liquid carrier is selected from the groupconsisting of FC-84, FC-72, RM-82, FC-75, RM-101, FC-43, RM-175,FC-5311, FC-5312, trimethylbicyclononane, dimethyladamantine andperfluorodecalin, or a combination thereof.
 5. The method of claim 1wherein said pharmaceutical preparation is oxygenated.
 6. The method ofclaim 1 in which the pharmaceutical preparation is administered at atemperature above the body temperature of the patient.
 7. The method ofclaim 1 in which the pharmaceutical preparation is administered at atemperature below the body temperature of the patient.
 8. The method ofclaim 1 wherein the biological agent is a solid.
 9. The method of claim8 wherein the biological agent is selected from the group consisting ofantibody-linked radionuclides, vasoconstrictors, vasodilators,bronchoconstrictors, bronchodilators, anti-cancer agents, surfactants,steroids, antibiotic agents, chemotactic agents, chemotherapeuticagents, contrast agents, antioxidants and antiproteases, or acombination thereof.
 10. The method of claim 8 wherein the biologicalagent comprises a chemotherapeutic agent.
 11. The method of claim 8wherein the biological agent comprises an antibiotic.
 12. The method ofclaim 8 wherein the biological agent comprises a bronchodilator.
 13. Themethod of claim 1 wherein the biological agent is in the form of animmiscible liquid.
 14. The method of claim 13 wherein the pharmaceuticalpreparation comprises an emulsion.
 15. The method of claim 14 whereinthe biological agent is selected from the group consisting ofantibody-linked radionuclides, vasoconstrictors, vasodilators,bronchoconstrictors, bronchodilators, anti-cancer agents, surfactants,steroids, antibiotic agents, chemotactic agents, chemotherapeuticagents, contrast agents, antioxidants and antiproteases, or acombination thereof.
 16. The method of claim 14 wherein the biologicalagent comprises a chemotherapeutic agent.
 17. The method of claim 14wherein the biological agent comprises an antibiotic.
 18. The method ofclaim 14 wherein the biological agent comprises a bronchodilator. 19.The method of claim 14 wherein the biological agent is dispersed in theperfluorochemical liquid carrier.
 20. The method of claim 19 wherein thebiological agent is selected from the group consisting ofantibody-linked radionuclides, vasoconstrictors, vasodilators,bronchoconstrictors, bronchodilators, anti-cancer agents, surfactants,steroids, antibiotic agents, chemotactic agents, chemotherapeuticagents, contrast agents, antioxidants and antiproteases, or acombination thereof.
 21. The method of claim 13 wherein the immiscibleliquid biological agent comprises the therapeutic or diagnostic agent inan aqueous medium.
 22. The method of claim 21 wherein said therapeuticor diagnostic agent is selected from the group consisting ofantibody-linked radionuclides, vasoconstrictors, vasodilators,bronchoconstrictors, bronchodilators, anti-cancer agents, surfactants,steroids, antibiotic agents, chemotactic agents, chemotherapeuticagents, contrast agents, antioxidants and antiproteases, or acombination thereof.
 23. A method for the delivery of a therapeutic ordiagnostic biological agent to pulmonary air passages of a patient inneed thereof comprising the steps of: combining a liquidperfluorochemical with an immiscible liquid to form an emulsion whereinsaid emulsion further comprises at least one therapeutic or diagnosticbiological agent; and administering the emulsion to the pulmonary airpassages of said patient.
 24. The method of claim 23 wherein said liquidperfluorochemical comprises a perfluorocarbon having a boiling pointgreater than about 55° C.
 25. The method of claim 23 wherein saidperfluorochemical liquid carrier is selected from the group consistingof FC-84, FC-72, RM-82, FC-75, RM-101, FC-43, RM-175, RC-5311, FC-5312,trimethylbicyclononane, dimethyladamantine and perfluorodecalin, or acombination thereof.
 26. The method of claim 23 wherein said emulsion isoxygenated.
 27. The method of claim 23 in which the emulsion isadministered at a temperature above the body temperature of the patient.28. The method of claim 23 in which the emulsion is administered at atemperature below the body temperature of the patient.
 29. The method ofclaim 23 wherein said immiscible liquid is aqueous.
 30. The method ofclaim 23 wherein the biological agent is selected from the groupconsisting of antibody-linked radionuclides, vasoconstrictors,vasodilators, bronchoconstrictors, bronchodilators, anti-cancer agents,surfactants, steroids, antibiotic agents, chemotactic agents,chemotherapeutic agents, contrast agents, antioxidants andantiproteases, or a combination thereof.
 31. The method of claim 23wherein the biological agent comprises a chemotherapeutic agent.
 32. Themethod of claim 23 wherein the biological agent comprises an antibiotic.33. The method of claim 23 wherein the biological agent comprises abronchodilator.
 34. The method of claim 23 wherein the biological agentis dispersed in the liquid perfluorochemical.
 35. The method of claim 34wherein the biological agent is selected from the group consisting ofantibody-linked radionuclides, vasoconstrictors, vasodilators,bronchoconstrictors, bronchodilators, anti-cancer agents, surfactants,steroids, antibiotic agents, chemotactic agents, chemotherapeuticagents, contrast agents, antioxidants and antiproteases, or acombination thereof.
 36. The method of claim 34 wherein the biologicalagent comprises a chemotherapeutic agent.
 37. The method of claim 34wherein the biological agent comprises an antibiotic.
 38. The method ofclaim 34 wherein the biological agent comprises a bronchodilator. 39.The method of claim 23 wherein the liquid comprises the therapeutic ordiagnostic agent in an aqueous medium.
 40. The method of claim 39wherein said therapeutic or diagnostic agent is selected from the groupconsisting of antibody-linked radionuclides, vasoconstrictors,vasodilators, bronchoconstrictors, bronchodilators, anti-cancer agents,surfactants, steroids, antibiotic agents, chemotactic agents,chemotherapeutic agents, contrast agents, antioxidants andantiproteases, or a combination thereof.
 41. A method for the deliveryof a therapeutic or diagnostic biological agent to pulmonary airpassages of a patient in need thereof comprising the steps of: combininga liquid perfluorochemical with at least one therapeutic or diagnosticbiological agent in solid form to provide a dispersion; andadministering the dispersion to the pulmonary air passages of saidpatient.
 42. The method of claim 41 wherein said liquidperfluorochemical comprises a perfluorocarbon having a boiling pointgreater than about 55° C.
 43. The method of claim 41 wherein said liquidperfluorochemical is selected from the group consisting of FC-84, FC-72,RM-82, FC-75, RM-101, FC-43, RM-175, FC-5311, FC-5312,trimethylbicyclononane, dimethyladamantine and perfluorodecalin, or acombination thereof.
 44. The method of claim 41 wherein said dispersionis oxygenated.
 45. The method of claim 41 wherein the solid biologicalagent comprises a powder.
 46. The method of claim 41 wherein the solidbiological agent is selected from the group consisting ofantibody-linked radionuclides, vasoconstrictors, vasodilators,bronchoconstrictors, bronchodilators, anti-cancer agents, surfactants,steroids, antibiotic agents, chemotactis agents, chemotherapeuticagents, contrast agents, antioxidants and antiproteases, or acombination thereof.
 47. The method of claim 41 wherein the solidbiological agent comprises a chemotherapeutic agent.
 48. The method ofclaim 41 wherein the solid biological agent comprises an antibiotic. 49.The method of claim 41 wherein the solid biological agent comprises abronchodilator.
 50. The method of claim 41 wherein the solid biologicalagent comprises a surfactant.